Search tips
Search criteria 


Logo of kirLink to Publisher's site
Kidney Int Rep. 2016 September; 1(3): 177–188.
Published online 2016 August 5. doi:  10.1016/j.ekir.2016.07.007
PMCID: PMC5601313

ISN Forefronts Symposium 2015: Nuclear Receptors and Diabetic Nephropathy

Bo Zheng,1,2,4 Lei Chen,1,2,3,4,* and Frank J. Gonzalez3,*


Diabetic nephropathy (DN) is the major reason for end-stage renal disease in the Western world. Patients with DN developed more severe cardiovascular complications with worse prognosis. In spite of tight blood pressure and glucose control through applying angiotensin Ⅱ receptor antagonism, angiotensin receptor inhibitors, and even direct renin inhibitors, the progression and development of DN has continued to accelerate. Nuclear receptors are, with few exceptions, ligand-depended transcription factors, some of which modulate genes involved in the transport and metabolism of carbohydrates or lipids, and in the modulation of inflammation. Considering the diverse biological functions of nuclear receptors, efforts have been made to explore their contributions to the pathogenesis of DN and their potential in therapeutic strategies. This review is mainly focused on the association between various nuclear receptors and the pathogenesis of DN, the potential beneficial effects of targeting these receptors for treating and preventing the progress of DN, and the important role that nuclear receptors may play in future therapeutic strategies for DN.

Keywords: diabetic nephropathy, ESRD

There exists a global pandemic in diabetes mellitus.1 Diabetic nephropathy (DN) develops in as many as 25% to 40% of diabetic patients after 25 years of uncontrolled and even treated diabetes. This makes DN the leading reason for the development of late-stage renal disease especially in the Western world2 where it accounts for approximately 22% of patients starting dialysis in Denmark3 and 44% in the USA.4 DN is characterized clinically by the increased blood pressure, occurrence of albuminuria, and a continual decrease of kidney function,2 and is associated with a remarkable increase in cardiovascular diseases5 and mortality.6 The annual mortality rate for patients with DN-induced renal disease is around 20%.7 During the last decade, there has been an 11-fold increase in spending for the treatment of patients with diabetes mellitus with concomitant DN and chronic kidney disease in the USA.8

The diffuse thickening of glomerular basement membrane together with nodular glomerulosclerosis is the major pathological feature of DN. During the initial stage of diabetic kidney disease, most patients only present modest proteinuria that deteriorates as the disease progresses. More advanced DN leads to primary and secondary pathological changes in the tubulointerstitial and vascular compartments, which is harmful to the maintenance of renal function. In a proportion of patients with clinical symptoms of DN, additional primary renal diseases (e.g., IgA nephropathy and renal arterial disease) may result from the diabetes mellitus-driven pathological abnormalities. Although the pathophysiology of DN is mainly due to hyperglycemia, it is also related to the wider network involving local and systemic processes,9, 10 some of which have been identified with cell and animal models, tissue samples, and human studies. For instance, in renal parenchymal cells, hyperglycemia induces abnormal activation of protein kinase C together with the increased expression of transforming growth factor β (TGFβ), matrix proteins fibronectin and collagen type IV, the dysregulation of nitric oxide, endothelial dysfunction and activation of the nuclear factor kappa B, and mitogen-activated protein kinase signaling.10, 11, 12 In addition, hyperglycemia can result in the overproduction of advanced glycation end products and induce overexpression of TGFβ.13 In spite of certain available treatments, the progression of DN continues to increase worldwide and thus novel therapeutic strategies are urgently needed.

Nuclear receptors are transcription factors that play various roles in embryo development, maintenance of the differentiated cellular phenotype, and manipulation of cell metabolism and death. This review mainly discusses the association between the pathogenesis of DN and nuclear receptors, including peroxisome proliferator–activated receptors (PPARs) α (NR1C1), β/δ (NR1C2), and γ (NR1C3); farnesoid X receptor (FXR, NR1H4); liver X receptors (LXRs, NR1H2, NR1H3); vitamin D receptor (VDR, NR1I1); hepatocyte nuclear factor 4α (HNF4α, NR2A1); retinoid X receptors (RXR, NR1F1, NR1F2, NR1F3); retinoid acid receptors (NR1B1, NR1B2, NR1B3); estrogen receptor (ER, NR3A1); and mineralocorticoid receptor (MR, NR3C2). Several studies have suggested that activation or inhibition of specific receptors could prevent the progression of DN, which implies that targeting nuclear receptors may be a potential therapeutic strategy for DN.

Nuclear Receptors


PPARs are ligand-activated transcriptional factors and include 3 related forms PPARα, PPARβ/δ, and PPARγ. Although they all have different tissue distributions, ligand selectivities, and biological effects, they play an important role in modulating lipid metabolism, adipogenesis, insulin sensitivity, inflammation, and blood pressure. Renal PPARα and PPARγ modulate energy utilization in the kidney by regulating fatty acid oxidation.14 Activated PPARα can stimulate fatty acid β-oxidation that can reduce the lipid content of tissues and blood, prevent the accumulation of lipid, and ameliorate lipotoxicity.15 Several kinases, including protein kinase A, protein kinase C, mitogen-activated protein kinases, and adenosine monophosphate kinase, were shown to phosphorylate PPARs resulting in changes in DNA-binding activity, ligand affinity, recruitment of transcriptional cofactors, and proteasome degradation in both a ligand-dependent or -independent manner.16 Phosphorylation by adenosine monophosphate kinase leads to increased PPARα and PPARγ signaling and enhances renal function in a type 2 diabetes mouse model by removing lipid accumulation in the kidney.15 Furthermore, the activation of PPARγ suppresses the renal expression of an α(1D)-adrenergic receptor that is overexpressed in the diabetic kidney.17

Chronic inflammation and oxidative stress play a pivotal role in the pathogenesis of chronic kidney disease. Activated PPARα can prevent overexpression of proinflammatory molecules.18 It was shown that the ligand activation of PPARα will increase the expression of fibroblast growth factor-21 (FGF-21), enhance the phosphatidylinositol-3 kinase/protein kinase B (AKT)/glycogen synthase kinase 3β (GSK-3β)/Fyn-mediated nuclear factor (erythroid-derived 2)-like 2 signal, and prevent the development of DN.19 PPARα activation improves lipotoxicity by activating adenosine monophosphate kinase-peroxisome proliferator-activated receptor g coactivator-1α (PGC-1α)-estrogen-related receptor-1α (ERR-1α)-forkhead box 03a (Fox03a) signaling and ameliorating glucose-induced matrix production and mesangial cell proliferation by inhibiting extracellular signal–regulated kinase 1/2 and phosphatidylinositol-3′-kinase/AKT activation, suggesting its potential for the treatment of DN.20, 21 In the absence of PPARα, the glomerular lesions displayed enhanced type IV collagen and TGFβ levels in DN, indicating that PPARα agonists can prevent glomerular matrix expansion together with apoptosis and the infiltration of inflammatory cells within the glomerulus.22 A recent study found that Huangkui capsule, an extract from Abelmoschus manihot (L.) medic, can ameliorate DN by increasing PPARα/PPARγ signaling leading to lowered endoplasmic reticulum (ER) stress in rats.23 It was reported that fenofibrate, a PPARα agonist, can dramatically decrease the excretion of urinary albumin and reduce mesangial matrix expansion and glomerular hypertrophy in the db/db diabetic mice model.24 Fenofibrate also improved insulin resistance and glomerular lesions in db/db mice,24 thus suggesting a renal protective role for fenofibrate in DN via the activation of PPARα in mesangial cells. A Fenofibrate Intervention and Event Lowering in Diabetes study further suggested that the early use of fenofibrate may prevent or postpone the development of DN.25

The protection provided by activated PPARγ is partially mediated by downregulating the level of renal disintegrin and metalloprotease-17 (ADAM17) and angiotensin-converting enzyme-2 (ACE2) shedding.26 Increased fibrosis in glomerular microenvironment is a remarkable characteristic of DN. Strong evidence suggests that PPARγ plays an important role during the pathogenesis of glomerulosclerosis. Treatment with PPARγ agonist ameliorated the hyperglycemia-mediated cannabinoid receptor type 1 (CB1R) signaling, inflammation, and glomerular fibrosis in diabetic animals.27, 28 PPARγ could prevent protein kinase A signaling, the activation of rat intraglomerular mesangial cells, TGFβ-induced accumulation of p-cyclic-AMP-responsive element binding protein and collagen-IV.29 PPARγ also negatively regulates inflammation through binding to the MIP3A promoter and downregulating the expression of macrophage inflammatory protein-3α (MIP-3α), a pathogenic mediator playing a crucial role in inflammation of DN.30 Other studies showed that PPARγ provides renoprotective action by negatively regulating the microsomal prostaglandin E synthase-1 (mPGES-1)/prostaglandin E2/prostaglandin E2 receptor 4 (EP4) pathway and restoring expression of the klotho axis in a PPARγ-dependent manner.31, 32 PPARγ may enhance the function of the angiotensin II receptor blocker by downregulating thioredoxin-interacting protein.33 PPARγ activated by pigment epithelium-derived factor could suppress the expression of the receptor for advanced glycation end products and decrease the reactive oxygen species (ROS), which subsequently prevents advanced glycation end product-induced apoptotic cell death in podocytes.34 Many studies were performed to separate the insulin sensitizing effects of PPARγ agonists from the transcriptional activation of genes that result in untoward side effects. This was achieved to some degree by using partial agonists that, compared with a full agonist, only partially activated the transcription of select genes.35

Among patients with type 2 diabetes, the polymorphism within PPARγ2 (Pro12Ala) provides protection against nephropathy progression and deterioration of renal function, independent of major confounders.36 However, the PPARγ2 (Pro12Ala) polymorphism may not be associated with the progression of DN in patients with type 1 diabetes.37 A meta-analysis showed that the PPARγ (Pro/Pro) genotype presented close association with DN risk in Caucasians, but the Ala/Ala genotype and Ala allele did not.38 Conversely, another meta-analysis indicated that the polymorphism in PPARγ (Pro12Ala) gene has no relationship with DN risk in Asians.39 The rs1801282 C>G variant in PPARγ was closely associated with decreased DN risk.40 However, further studies revealed that the PPARγ2 Ala12 variant provided renal protection by reducing the occurrence of albuminuria among patients with type 2 diabetes.41, 42

PPARβ/δ agonist treatment inhibited glomerular mesangial expansion, albuminuria, and the accumulation of type IV collagen with no effect on blood glucose levels in streptozotocin-treated diabetic mice.43 The activation of PPARβ/δ is necessary for treating DN by preventing inflammation and activating of its downstream receptor for advanced glycation end product or nuclear factor kappa B signals.43, 44 PPARβ/δ agonist could postpone diabetes-induced nephrin loss, enhance podocyte integrity, and prevent albuminuria subsequently.45


LXRs were first identified as orphan receptors when discovered, and then subsequently found to be targets of oxysterol metabolites of cholesterol.46 LXRs include LXRα and LXRβ that have different tissue distribution patterns, but have been most extensively studied in the liver. LXRs might have a role in regulating lipid metabolism and maintaining the function of proximal tubule as well as podocytes by downregulating the expression of nephrin.47 The administration of the LXR agonist T0901317 could increase cholesterol efflux via activating the ATP-binding cassette transporter A1 (ABCA1) in cultured glomerular mesangial cells, and enhance the expression of stearoyl-CoA desaturase-1 through increasing the level of sterol regulatory element-binding protein 1c (SREBP-1c) within proximal tubules.48, 49 LXRα/SREBP-1 signaling also has the capability of regulating the expression of many genes involved in fatty acid and triglyceride synthesis.50 Nε-(carboxymethyl) lysine, a member of the advanced glycation end product family, modulates cholesterol metabolism through stimulating LXR and SREBP-2, which resulted in a reduction in ABCA1-mediated cholesterol efflux and the accumulation of lipid in human kidney-2 (HK-2) cells.51 Bilirubin improved dyslipidemia and renal disfunction via suppressing the expression of LXRα and SREBP-1 and decreasing ROS.52 Furthermore, the activation of LXR may prevent inflammation and the development of DN.46, 53 T0901317 could prevent the development of albuminuria, glomerular mesangial expansion, and interstitial fibrosis by decreasing osteopontin level, macrophage infiltration, and expression of inflammatory genes, such as monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor α (TNFα), and TGFβ, in the diabetic kidney.46 Knockdown of LXRα expression resulted in loss of the anti-inflammatory effect of anthocyanins, and further studies demonstrated that LXRα might participate in the anthocyanin-induced action of decreasing intercellular adhesion molecule 1, MCP1, and TGFβ1 via inhibiting the nuclear translocation of nuclear factor kappa B protein.54 Expression of LXRα in macrophage of transgenic mice markedly ameliorated hyperlipidemic-hyperglycemic nephropathy by suppressing glycated or acetylated low-density lipoprotein-induced cytokines and ROS in macrophages.55 Recently, accelerated mesangial matrix expansion and glomerular lipid accumulation were observed in Lxra/Lxrb-null diabetic mice, in coupling with the enrichment of oxidative stress and inflammatory markers. Moreover, treatment with a synthetic oxysterol, N,N-dimethyl-3beta-hydroxycholenamide, an LXR agonist, dramatically ameliorated the excretion of albumin and nephrin, the levels of glomerular lipids and plasma triacylglycerol and cholesterol. In addition, the decreased level of kidney inflammatory and oxidative stress markers was observed upon N,N-dimethyl-3beta-hydroxycholenamide treatment.47 Together, these results indicate that the activity of LXR is necessary for both normal and diabetic kidney.


FXR was first thought to be an orphan receptor when discovered. However, further studies revealed that bile acid-induced activation of FXR is important for bile-acid synthesis and transport in the liver and intestine.56, 57, 58 Endogenous ligands for FXR include the primary bile acids, taurocholic acid, chenodeoxycholic acid, and cholic acid. FXR is expressed at highest levels in the liver and intestine, and at lower levels in adrenal gland and other tissues; it is also highly expressed in the kidney.59 It also plays a pivotal role in lipid, glucose, and bile acid homeostasis in the enterohepatic system.60, 61 Furthermore, FXR agonists may provide protection against liver fibrosis.62, 63 FXR agonists downregulate renal overexpression of SREBP-1 that could lead to lipid accumulation during the development of nephropathy and regulating renal lipid metabolism. The activation of FXR could prevent the induction of profibrotic growth factors, proinflammatory cytokines, and oxidative stress-related enzymes in the kidney, and thus improve glomerulosclerosis and proteinuria.64 Furthermore, the activation of FXR could suppress the development of nephropathy in type 1 diabetes via blocking diabetes-induced dysregulation of lipid metabolism, fibrosis, inflammation, and oxidative stress in the kidney.65 Recently, the adipocytokine visfatin was found to have a crucial role in the development of DN, at least partly, through enhancing high glucose-induced human mesangial cell inflammation, fibrosis, and proliferation in the absence of FXR.66


Vitamin D is necessary for the metabolism of calcium and bone. It was reported that vitamin D deficiency was closely associated with increased risk for diabetes development, diabetes complications, and cardiovascular disease.67 A meta-analysis including 5 observational studies suggested that children treated with vitamin D are less likely to develop type 1 diabetes mellitus.68 The fact that the lack of vitamin D impairs insulin synthesis and secretion suggested its close association with the pathogenesis of type 2 diabetes, although the mechanistic link has not been well established.69

The protective activities of VDR may result from the inhibition of the renin-angiotensin system, reduction of proteinuria, and regulation of cell proliferation and differentiation. A recent study suggested that vitamin D and its receptor might modulate the progression of DN via regulating the TGFβ levels, the expression of angiotensinogen, and apoptosis of podocytes through the nuclear factor kappa B pathway.70 Activated macrophages 1 (M1) and activated macrophages 2 (M2) have opposing roles in inflammation. M1 activation was inhibited by 1,25-dihydroxyvitamin D3, a VDR agonist, while M2 was activated.71 Another study reported that vitamin D can switch the M1 phenotype to M2 via activating the VDR-PPARγ pathway.72 Diabetic Vdr null mice developed more severe nephropathy than wild-type mice as renin-angiotensin system activation was enhanced, suggesting that VDR protects the kidney from hyperglycemia-induced injury through inhibiting renin-angiotensin system activity.73 These data indicated that the combination of renin-angiotensin system inhibitors and a VDR activator might be of value to improve DN-induced albuminuria.74 A randomized clinical trial revealed that daily treatment of paricalcitol, a selective VDR agonist, could ameliorate residual albuminuria in ACE inhibitor (ACEI)- or angiotensin II type 1 receptor blockade (ARB)-treated DN patients, especially in those with high dietary sodium intake. These data suggested that the combination of paricalcitol and ACEI or ARBs could effectively reduce residual albuminuria, which may be applied as a new strategy in the treatment of DN.75 Wnt/β-catenin signal-related epithelial-mesenchymal transition was reportedly involved in the pathogenesis of DN.76 A recent study documented that VDR could decrease the expression of β-catenin by replacing β-catenin complexing with transcription factor 4 (TCF-4), therefore blocking Wnt/β-catenin signaling.77

Podocyte injury is one of the causes of DN.78 VDR activation in podocytes plays an important role in preventing the kidney from diabetic damage.79 Calcitriol or a vitamin D analog can improve podocyte damage by inhibiting the expression of transient receptor potential cation channel. subfamily C. member 6 (TRPC6) during the early stage of DN in a rat model.78 1,25-D3 treatment ameliorated proteinuria in 25-hydroxy-1α-hydroxylase conventional knockout mice coupled with increasing heparanase expression, suggesting that vitamin D mediated the emergence of proteinuria by reducing heparanase levels in podocytes.80 Furthermore, vitamin D analogs provide protection against lesion of renal barrier by maintaining and reactivating the expression of podocalyxin, a specialized component of podocytes.81

The anti-inflammatory action of vitamin D is due to its influence on the crosstalk between signal transducer and activator of transcription 5 and VDR.82 A functional polymorphism of the VDR gene may result in individual susceptibility to DN, and a meta-analysis suggested the correlation of a Fok1 single-nucleotide polymorphism with DN susceptibility in Caucasians.83 Another study showed that a BsmI single-nucleotide polymorphism polymorphism in Han Chinese people was responsible for the type 2 diabetes-related albuminuria.84


MR regulates the reabsorption of sodium and water and secretion of potassium via control of the epithelial ion channel. The representative agonist and antagonist of MR are respectively aldosterone and spironolactone. However, mineralocorticoids could not only regulate the transport of epithelial salt, extracellular volume, and blood pressure, but also inflammation and fibrosis either directly or indirectly. Emerging evidence indicates that aldosterone participates in the pathogenesis of kidney disease in a nonepithelial MR-dependent manner.85 Some studies also reported that aldosterone impairs insulin sensitivity through MR activation in adipocytes in vitro, which indicates that aldosterone may play an important role in the development of diabetes.86, 87 Interestingly, leptin, which is upregulated in diabetic obese models, stimulates aldosterone production in vitro in human adrenocortical cells and in vivo in mice. In addition, aldosterone increases fibrosis by upregulating the production of TGFβ1, ROS, plasminogen activator inhibitor 1 (PAI-1), and the enrichment of collagen protein, which can be blocked by MR antagonist.88 Integrin β1 and β3 expression in podocytes is essential to the integrity of a glomerular structure. In a high glucose environment, the expression of integrin β1 in cultured podocytes is markedly decreased, accompanied with an increase of integrin β3, and a recent study suggested that spironolactone inhibited cell motility and stabilized podoctyes cultured in a high glucose environment, in part by normalizing the level of integrin β1 and β3.89 Treatment with spironolactone provides protection for podocytes and inhibits the development of morphological changes associated with DN, probably by the inhibition of TGFβ1 mRNA expression.90 Spironolactone could inhibit MR-induced ROS production and hyperglycemia-mediated podocyte lesions in diabetics.91 Recent studies revealed a crucial role for aldosterone in the pathogenesis of DN, which has no effect on angiotensin II and blood pressure levels.92 Another study enrolling type 2 diabetic patients also demonstrated that patients who developed aldosterone escape, an increase in aldosterone levels during long-term treatment of ACEIs, suffered more severe albuminuria than did patients without aldosterone escape. However, in combination with spironolactone treatment a further decrease in albuminuria was noted in these patients.92 Furthermore, the incidence of severe hyperkalemia, which is the major side effect of spironolactone treatment in clinical trials, is low, probably resulting from the monitoring of dietary intake of potassium and diuretics in clinical observation. However, the liberalized usage of spironolactone is strictly forbidden for patients whose kidney function was reduced.92 It was suggested that alterations of Na/K ATPase levels might be a new pathophysiological feature for DN. The ability of aldosterone antagonists to decrease Na/K ATPase protein levels and enzyme mislocation that are increased in diabetes may suggest a new pharmaceutical use in the treatment of DN.93

Other Nuclear Receptors

The sex hormone estrogen has several functions including control of bone growth, modulation of differentiation and function of the reproductive tract, and memory storage.94, 95 Estrogen exerts its biological activity through the interaction with classic estrogen receptors, ERα and ERβ.96 It is generally known that females have a lower chance of suffering from nondiabetic chronic kidney disease than males.97, 98, 99, 100 Although the contribution of gender to the progression of type 1 or type 2 diabetic renal disease is still uncertain,100, 101 some studies suggested that DN even progresses faster in males than females.102, 103, 104, 105, 106, 107, 108 However, other results indicated an acceleration of disease progression in females,109, 110, 111, 112 whereas some studies reported no difference between men and women.113, 114, 115 Because ERβ can regulate cell apoptosis and cycle in tumor cells116 and ERβ protein expression is increased in podocytes treated with estrogen,117 estrogens could protect against podocytes apoptosis.117 The fact that podocytes isolated from estrogen-treated diabetic mice showed an increase in the level of AKT phosphorylation indicates that estrogen may achieve such an effect by activating the phosphatidylinositol-3′-kinase-AKT axis.117 The increased ERβ protein level in podocytes could manipulate the cell cycle and increase cell survival rates, suggesting that estrogen has the capability of preventing podocyte loss during diabetes-mediated kidney disease.117 Several lines of evidence revealed that TGFβ promotes diabetic kidney disease, at least partly through inducing cell apoptosis and podocyte clearance.118, 119, 120, 121 Relevant data showed that E2 treatment provides protection for podocytes against TGFβ or (TNFα)-induced apoptosis in vitro. Other studies suggested that treatment with E2 could be helpful to prevent albuminuria, glomerulosclerosis, and tubulointerstitial fibrosis in the initial stages of diabetes.122, 123, 124 However, some studies did not support the protective effects of estrogens for the patients with diabetic kidney. A recent study found that elevated serum concentrations of phytoestrogens are positively correlated with the severity of diabetic renal disease, suggesting the potential harmful effect of phytoestrogens.125

Retinoic acid is the active metabolite of vitamin A, which plays a pivotal role in many physiological processes including but not limited to energy metabolism. Retinoic acid can facilitate the formation of retinoic acid receptor/RXR heterodimers or RXR/RXR homodimers, which could bind to the retinoic acid response element upstream of retinoic acid target gene promoters and modulate their transcription in the presence of specific ligands.126, 127 PPARs or other nuclear receptors can also form heterodimers with RXR, and modulate the biological function of several hormones and drugs.128, 129 For example, the RXRα:RXRα homodimer and RXRα:PPARγ are needed to recruit their coactivators to initiate the transcription of target genes130 through binding to their response elements.131 Considering that PPARγ is a key target in the treatment of DN, RXRα targeting may become a new treatment strategy. Furthermore, RXRs can be used as permissive heterodimers with LXR, FXR, PXR, and constitutive androstane receptor (CAR), or as nonpermissive heterodimer interacting with VDR, and as conditional heterodimers together with retinoid acid receptor or thyroid receptor (TR).132 On the other hand, because of the nature of its partners, the activation state of RXR changes in different heterodimers.133 Three RXR subtypes were identified as RXRα, RXRβ, and RXRγ.134, 135 As compared with the universal distribution of RXRα and RXRβ, RXRγ is only detected in some specific tissues.136 RXRα also showed antioxidants properties and played an important role in the pathogenesis of diabetic retinopathy.137 RXRγ encoded by RXRG gene was also involved in the pathogenesis of DN.138

Orphan Receptors

HNF4α is expressed at high levels in the liver, kidney, and intestine, and controls the expression of a large gene set including those involved in glucose and fatty acid metabolism, urea biosynthesis, cholesterol metabolism, blood coagulation, hepatitis B virus infection, and hepatocyte differentiation.139 Dysfunction of HNF4α can lead to metabolic disease. Notably, genetic mutations in HNF4α result in maturity-onset diabetes of the young-1.140 The expression of the HNF4α gene is significantly decreased in the kidney and liver in 2 diabetic rodent models.141Additionally, HNF4α is decreased in kidneys of patients with DN. HNF4α negatively regulates the transcription of stromal interacting molecule-1, which is increased in a high glucose environment in mesangial cells.142 Blockage of HNF4α in mesangial cells might be a candidate therapeutic strategy for DN, as the stromal interacting molecule-1-gated store-operated Ca(2+) entry pathway in mesangial cells was recently found to be antifibrotic.142, 143, 144

HNF1α is a homeodomain-containing transcription factor that plays an important role for modulating different metabolic functions in the liver, pancreatic islet, kidney, and intestine.145 Maturity-onset diabetes of the young-3 result from rare mutations in HNF1A.146, 147 Although genetic variants in HNF1β are not a major cause of maturity-onset diabetes of the young or DN, they might lead to the manifestation of disease in Chinese.148


The systematic and renal effects of nuclear hormone receptor activation in the context of diabetic nephropathy are shown in Table 1. Among the highlights, the fibrate class of PPARα agonists have long been prescribed to reduce triglyceride (TG), increase high-density lipoprotein-C (HDL-C), and improve cardiovascular outcomes in diabetic patients,149, 150 mainly by activating the expression of genes involved in lipid homeostasis.151 PPARα agonists also have the ability to improve renal lesion in DN animal models; however, whether a similar efficacy is also observed in diabetic patients remains to be determined.152 The VDR agonist calcitriol might ameliorate albuminuria by reducing urinary angiotensinogen levels.80 Furthermore, a combination treatment of mineralocorticoid receptor blockers with ACEI or ARB therapy has recently emerged, but the long-term efficacy and safety of such treatment has not been established.153 Although only a few nuclear receptors were evaluated as potential targets for the treatment of DN, clinical trials and animal studies have put more focus into the function of nuclear hormone receptors for protection against kidney disease. Identifying the mechanism by which activation of nuclear hormone receptors modulate kidney disease and determining their roles in the pathogenesis of DN, and the ultimate application of nuclear receptor targeting as a therapeutic strategy require considerably more experimentation.

Table 1
Systematic and renal effects of nuclear hormone receptor activation in the context of diabetic nephropathy


All the authors declared no competing interests.


1. van Dieren S., Beulens J.W., van der Schouw Y.T. The global burden of diabetes and its complications: an emerging pandemic. Eur J Cardiovasc Prev Rehabil. 2010;17(suppl 1):S3–S8. [PubMed]
2. Parving H.-H., Mauer M., Ritz E. 8th ed. Saunders; Philadelphia: 2008. Diabetic Nephropathy.
3. Nephrology TDSo. Danish National Registry Annual Report 2007; 2008.
4. U.S. Renal Data System ADR. Atlas of End-Stage Renal Disease in the United States; 2008.
5. Jensen T., Borch-Johnsen K., Kofoed-Enevoldsen A., Deckert T. Coronary heart disease in young type 1 (insulin-dependent) diabetic patients with and without diabetic nephropathy: incidence and risk factors. Diabetologia. 1987;30:144–148. [PubMed]
6. Borch-Johnsen K., Kreiner S. Proteinuria: value as predictor of cardiovascular mortality in insulin dependent diabetes mellitus. Brit Med J. 1987;294:1651–1654. [PubMed]
7. Reidy K., Kang H.M., Hostetter T., Susztak K. Molecular mechanisms of diabetic kidney disease. J Clin Invest. 2014;124:2333–2340. [PubMed]
8. National Institutes of Health NIoDaDaKD Epidemiology of Kidney Disease in the United States. United States Renal Data System, 2014 Annual Data Report. 2014 [PubMed]
9. Sharma K., Karl B., Mathew A.V. Metabolomics reveals signature of mitochondrial dysfunction in diabetic kidney disease. J Am Soc Nephrol. 2013;24:1901–1912. [PubMed]
10. Griffin T.P., Martin W.P., Islam N. The promise of mesenchymal stem cell therapy for diabetic kidney disease. Curr Diab Rep. 2016;16:42. [PubMed]
11. Noh H., King G.L. The role of protein kinase C activation in diabetic nephropathy. Kidney Int Suppl. 2007;206:S49–S53. [PubMed]
12. Derubertis F.R., Craven P.A. Activation of protein kinase C in glomerular cells in diabetes. Mechanisms and potential links to the pathogenesis of diabetic glomerulopathy. Diabetes. 1994;43:1–8. [PubMed]
13. Yang J., Zhu T., Liu X. Heat shock protein 70 protects rat peritoneal mesothelial cells from advanced glycation end-products-induced epithelial-to-mesenchymal transition through mitogen-activated protein kinases/extracellular signal-regulated kinases and transforming growth factor-beta/Smad pathways. Mol Med Rep. 2015;11:4473–4481. [PubMed]
14. Wu J., Chen L., Zhang D. Peroxisome proliferator-activated receptors and renal diseases. Front Biosci. 2009;14:995–1009. [PubMed]
15. Koh E.S., Lim J.H., Kim M.Y. Anthocyanin-rich Seoritae extract ameliorates renal lipotoxicity via activation of AMP-activated protein kinase in diabetic mice. J Transl Med. 2015;13:203. [PubMed]
16. Diradourian C., Girard J., Pegorier J.P. Phosphorylation of PPARs: from molecular characterization to physiological relevance. Biochimie. 2005;87:33–38. [PubMed]
17. Zhao X., Zhang Y., Leander M. Altered expression profile of renal alpha(1D)-adrenergic receptor in diabetes and its modulation by PPAR agonists. J Diab Res. 2014;2014:725634. [PMC free article] [PubMed]
18. Ibarra-Lara M.L., Sanchez-Aguilar M., Soria E. Peroxisome proliferator-activated receptors (PPAR) downregulate the expression of pro-inflammatory molecules in an experimental model of myocardial infarction. Can J Physiol Pharmacol. 2016;94:634–642. [PubMed]
19. Cheng Y., Zhang J., Guo W. Up-regulation of Nrf2 is involved in FGF21-mediated fenofibrate protection against type 1 diabetic nephropathy. Free Radic Biol Med. 2016;93:94–109. [PubMed]
20. Hong Y.A., Lim J.H., Kim M.Y. Fenofibrate improves renal lipotoxicity through activation of AMPK-PGC-1alpha in db/db mice. PLoS One. 2014;9:e96147. [PubMed]
21. Zeng R., Xiong Y., Zhu F. Fenofibrate attenuated glucose-induced mesangial cells proliferation and extracellular matrix synthesis via PI3K/AKT and ERK1/2. PLoS One. 2014;9:e96147. [PubMed]
22. Park C.W., Kim H.W., Ko S.H. Accelerated diabetic nephropathy in mice lacking the peroxisome proliferator-activated receptor alpha. Diabetes. 2006;55:885–893. [PubMed]
23. Ge J., Miao J.J., Sun X.Y., Yu J.Y. Huangkui capsule, an extract from Abelmoschus manihot (L.) medic, improves diabetic nephropathy via activating peroxisome proliferator-activated receptor (PPAR)-alpha/gamma and attenuating endoplasmic reticulum stress in rats. J Ethnopharmacol. 2016;189:238–249. [PubMed]
24. Park C.W., Zhang Y., Zhang X. PPARalpha agonist fenofibrate improves diabetic nephropathy in db/db mice. Kidney Int. 2006;69:1511–1517. [PubMed]
25. Sacks F.M. After the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study: implications for fenofibrate. Am J Cardiol. 2008;102:34L–40L. [PubMed]
26. Chodavarapu H., Grobe N., Somineni H.K. Rosiglitazone treatment of type 2 diabetic db/db mice attenuates urinary albumin and angiotensin converting enzyme 2 excretion. PLoS One. 2013;8:e62833. [PubMed]
27. Lin C.L., Hsu Y.C., Lee P.H. Cannabinoid receptor 1 disturbance of PPARgamma2 augments hyperglycemia induction of mesangial inflammation and fibrosis in renal glomeruli. J Mol Med (Berl) 2014;92:779–792. [PubMed]
28. Bottinger E.P., Bitzer M. TGF-beta signaling in renal disease. J Am Soc Nephrol. 2002;13:2600–2610. [PubMed]
29. Zou R., Xu G., Liu X.C. PPARgamma agonists inhibit TGF-beta-PKA signaling in glomerulosclerosis. Acta Pharmacol Sin. 2010;31:43–50. [PubMed]
30. Qi W., Holian J., Tan C.Y. The roles of Kruppel-like factor 6 and peroxisome proliferator-activated receptor-gamma in the regulation of macrophage inflammatory protein-3alpha at early onset of diabetes. Int J Biochem Cell Biol. 2011;43:383–392. [PubMed]
31. Sun Y., Jia Z., Liu G. PPARgamma agonist rosiglitazone suppresses renal mPGES-1/PGE2 pathway in db/db mice. PPAR Res. 2013;2013:612971. [PubMed]
32. Huang K.C., Cherng Y.G., Chen L.J. Rosiglitazone is effective to improve renal damage in type-1-like diabetic rats. Horm Metab Res. 2014;46:240–244. [PubMed]
33. Wu J., Lin H., Liu D. The protective effect of telmisartan in type 2 diabetes rat kidneys is related to the downregulation of thioredoxin-interacting protein. J Endocrinol Invest. 2013;36:453–459. [PubMed]
34. Ishibashi Y., Matsui T., Ohta K. PEDF inhibits AGE-induced podocyte apoptosis via PPAR-gamma activation. Microvascular Res. 2013;85:54–58. [PubMed]
35. Kroker A.J., Bruning J.B. Review of the structural and dynamic mechanisms of PPARγ partial agonism. PPAR Res. 2015;2015:816856. [PubMed]
36. Lapice E., Monticelli A., Cocozza S. The PPARγ2 Pro12Ala variant is protective against progression of nephropathy in people with type 2 diabetes. J Transl Med. 2015;13:85. [PubMed]
37. Yang B., Zhao H., Millward B.A. The rate of decline of glomerular filtration rate may not be associated with polymorphism of the PPARγ2 gene in patients with type 1 diabetes and nephropathy. PPAR Res. 2014;2014:523584. [PubMed]
38. Zhou T.B., Guo X.F., Yin S.S. Association of peroxisome proliferator-activated receptor gamma Pro12Ala gene polymorphism with type 2 diabetic nephropathy risk in Caucasian population. J Recept Signal Transduct Res. 2014;34:180–184. [PubMed]
39. Liu G., Zhou T.B., Jiang Z. Relationship between PPARgamma Pro12Ala gene polymorphism and type 2 diabetic nephropathy risk in Asian population: results from a meta-analysis. J Recep Signal Transduct Res. 2014;34:131–136. [PubMed]
40. Li T., Shi Y., Yin J. The association between lipid metabolism gene polymorphisms and nephropathy in type 2 diabetes: a meta-analysis. Int Urol Nephrol. 2015;47:117–130. [PubMed]
41. Lapice E., Cocozza S., Riccardi G., Vaccaro O. Comment on: Zhang et al. Peroxisome proliferator-activated receptor gamma polymorphism Pro12Ala is associated with nephropathy in type 2 diabetes: evidence from meta-analysis of 18 studies. Diabetes Care 2012;35:1388–1393. Diabetes Care. 2013;36:e18. [PubMed]
42. De Cosmo S., Prudente S., Lamacchia O. PPARgamma2 P12A polymorphism and albuminuria in patients with type 2 diabetes: a meta-analysis of case-control studies. Nephrol Dial Transplant. 2011;26:4011–4016. [PubMed]
43. Matsushita Y., Ogawa D., Wada J. Activation of peroxisome proliferator-activated receptor delta inhibits streptozotocin-induced diabetic nephropathy through anti-inflammatory mechanisms in mice. Diabetes. 2011;60:960–968. [PubMed]
44. Liang Y.J., Chen S.A., Jian J.H. Peroxisome proliferator-activated receptor delta downregulates the expression of the receptor for advanced glycation end products and pro-inflammatory cytokines in the kidney of streptozotocin-induced diabetic mice. Eur J Pharmaceut Sci. 2011;43:65–70. [PubMed]
45. Lee E.Y., Kim G.T., Hyun M. Peroxisome proliferator-activated receptor-delta activation ameliorates albuminuria by preventing nephrin loss and restoring podocyte integrity in type 2 diabetes. Nephrol Dial Transplant. 2012;27:4069–4079. [PubMed]
46. Tachibana H., Ogawa D., Matsushita Y. Activation of liver X receptor inhibits osteopontin and ameliorates diabetic nephropathy. J Am Soc Nephrol. 2012;23:1835–1846. [PubMed]
47. Patel M., Wang X.X., Magomedova L. Liver X receptors preserve renal glomerular integrity under normoglycaemia and in diabetes in mice. Diabetologia. 2014;57:435–446. [PubMed]
48. Wu J., Zhang Y., Wang N. Liver X receptor-alpha mediates cholesterol efflux in glomerular mesangial cells. Am J Physiol Renal Physiol. 2004;287:F886–F895. [PubMed]
49. Zhang Y., Zhang X., Chen L. Liver X receptor agonist TO-901317 upregulates SCD1 expression in renal proximal straight tubule. Am J Physiol Renal Physiol. 2006;290:F1065–F1073. [PubMed]
50. Lee J.H., Jung J.Y., Jang E.J. Combination of honokiol and magnolol inhibits hepatic steatosis through AMPK-SREBP-1 c pathway. Exp Biol Med (Maywood) 2015;240:508–518. [PubMed]
51. Sun H., Yuan Y., Sun Z. Update on mechanisms of renal tubule injury caused by advanced glycation end products. Biomed Res Int. 2016;2016:5475120. [PubMed]
52. Xu J., Lee E.S., Baek S.H. Effect of bilirubin on triglyceride synthesis in streptozotocin-induced diabetic nephropathy. J Korean Med Sci. 2014;29(suppl 2):S155–S163. [PubMed]
53. Saraheimo M., Teppo A.M., Forsblom C. Diabetic nephropathy is associated with low-grade inflammation in type 1 diabetic patients. Diabetologia. 2003;46:1402–1407. [PubMed]
54. Du C., Shi Y., Ren Y. Anthocyanins inhibit high-glucose-induced cholesterol accumulation and inflammation by activating LXRalpha pathway in HK-2 cells. Drug Des Devel Ther. 2015;9:5099–5113. [PMC free article] [PubMed]
55. Kiss E., Kranzlin B., Wagenblabeta K. Lipid droplet accumulation is associated with an increase in hyperglycemia-induced renal damage: prevention by liver X receptors. Am J Pathol. 2013;182:727–741. [PubMed]
56. Makishima M., Okamoto A.Y., Repa J.J. Identification of a nuclear receptor for bile acids. Science. 1999;284:1362–1365. [PubMed]
57. Parks D.J., Blanchard S.G., Bledsoe R.K. Bile acids: natural ligands for an orphan nuclear receptor. Science. 1999;284:1365–1368. [PubMed]
58. Wang H., Chen J., Hollister K. Endogenous bile acids are ligands for the nuclear receptor FXR/BAR. Mol Cell. 1999;3:543–553. [PubMed]
59. Bookout A.L., Jeong Y., Downes M. Anatomical profiling of nuclear receptor expression reveals a hierarchical transcriptional network. Cell. 2006;126:789–799. [PubMed]
60. Kalaany N.Y., Mangelsdorf D.J. LXRS and FXR: the yin and yang of cholesterol and fat metabolism. Annu Rev Physiol. 2006;68:159–191. [PubMed]
61. Matsubara T., Li F., Gonzalez F.J. FXR signaling in the enterohepatic system. Mol Cell Endocrinol. 2013;368:17–29. [PubMed]
62. Fiorucci S., Rizzo G., Antonelli E. A farnesoid x receptor-small heterodimer partner regulatory cascade modulates tissue metalloproteinase inhibitor-1 and matrix metalloprotease expression in hepatic stellate cells and promotes resolution of liver fibrosis. J Pharmacol Exp Ther. 2005;314:584–595. [PubMed]
63. Fiorucci S., Rizzo G., Antonelli E. Cross-talk between farnesoid-X-receptor (FXR) and peroxisome proliferator-activated receptor gamma contributes to the antifibrotic activity of FXR ligands in rodent models of liver cirrhosis. J Pharmacol Exp Ther. 2005;315:58–68. [PubMed]
64. Jiang T., Wang X.X., Scherzer P. Farnesoid X receptor modulates renal lipid metabolism, fibrosis, and diabetic nephropathy. Diabetes. 2007;56:2485–2493. [PubMed]
65. Wang X.X.X., Jiang T., Shen Y. Diabetic nephropathy is accelerated by farnesoid X receptor deficiency and inhibited by farnesoid X receptor activation in a type 1 diabetes model. Diabetes. 2010;59:2916–2927. [PubMed]
66. Zhou B., Feng B., Qin Z. Activation of farnesoid X receptor downregulates visfatin and attenuates diabetic nephropathy. Mol Cell Endocrinol. 2016;419:72–82. [PubMed]
67. Alam U., Arul-Devah V., Javed S., Malik R.A. Vitamin D and diabetic complications: true or false prophet? Diabetes Ther. 2016;7:11–26. [PubMed]
68. Zipitis C.S., Akobeng A.K. Vitamin D supplementation in early childhood and risk of type 1 diabetes: a systematic review and meta-analysis. Arch Dis Child. 2008;93:512–517. [PubMed]
69. Mathieu C., Gysemans C., Giulietti A. Vitamin D and diabetes. Diabetologia. 2005;48:1247–1257. [PubMed]
70. Xu L, Zhang P, Guan H, et al. Vitamin D and its receptor regulate lipopolysaccharide-induced transforming growth factor-beta, angiotensinogen expression and podocytes apoptosis through the nuclear factor-kappaB pathway [e-pub ahead of print]. J Diab Invest. Accessed June 1, 2016. [PMC free article] [PubMed]
71. Zhang X.L., Guo Y.F., Song Z.X., Zhou M. Vitamin D prevents podocyte injury via regulation of macrophage M1/M2 phenotype in diabetic nephropathy rats. Endocrinology. 2014;155:4939–4950. [PubMed]
72. Zhang X., Zhou M., Guo Y. 1,25-Dihydroxyvitamin D(3) promotes high glucose-induced M1 macrophage switching to M2 via the VDR-PPARgamma signaling pathway. Biomed Res Int. 2015;2015:157834. [PubMed]
73. Zhang Z., Sun L., Wang Y. Renoprotective role of the vitamin D receptor in diabetic nephropathy. Kidney Int. 2008;73:163–171. [PubMed]
74. Tiryaki O., Usalan C., Sayiner Z.A. Vitamin D receptor activation with calcitriol for reducing urinary angiotensinogen in patients with type 2 diabetic chronic kidney disease. Ren Fail. 2016;38:222–227. [PubMed]
75. de Zeeuw D., Agarwal R., Amdahl M. Selective vitamin D receptor activation with paricalcitol for reduction of albuminuria in patients with type 2 diabetes (VITAL study): a randomised controlled trial. Lancet. 2010;376:1543–1551. [PubMed]
76. Shapiro I.M., Cheng A.W., Flytzanis N.C. An EMT-driven alternative splicing program occurs in human breast cancer and modulates cellular phenotype. PLoS Genet. 2011;7:e1002218. [PubMed]
77. Palmer H.G., Gonzalez-Sancho J.M., Espada J. Vitamin D(3) promotes the differentiation of colon carcinoma cells by the induction of E-cadherin and the inhibition of beta-catenin signaling. J Cell Biol. 2001;154:369–387. [PubMed]
78. Zhang X., Song Z., Guo Y., Zhou M. The novel role of TRPC6 in vitamin D ameliorating podocyte injury in STZ-induced diabetic rats. Mol Cell Biochem. 2015;399:155–165. [PubMed]
79. Wang Y., Deb D.K., Zhang Z. Vitamin D receptor signaling in podocytes protects against diabetic nephropathy. J Am Soc Nephrol. 2012;23:1977–1986. [PubMed]
80. Garsen M., Sonneveld R., Rops A.L. Vitamin D attenuates proteinuria by inhibition of heparanase expression in the podocyte. J Pathol. 2015;237:472–481. [PubMed]
81. Verouti S.N., Tsilibary E.C., Fragopoulou E. Vitamin D receptor activators upregulate and rescue podocalyxin expression in high glucose-treated human podocytes. Nephron Exp Nephrol. 2012;122:36–50. [PubMed]
82. Yang M.X., Yang B., Gan H. Anti-inflammatory effect of 1,25-dihydroxyvitamin D-3 is associated with crosstalk between signal transducer and activator of transcription 5 and the vitamin D receptor in human monocytes. Exp Ther Med. 2015;9:1739–1744. [PubMed]
83. Liu Z., Liu L., Chen X. Associations study of vitamin D receptor gene polymorphisms with diabetic microvascular complications: a meta-analysis. Gene. 2014;546:6–10. [PubMed]
84. Zhang H., Wang J., Yi B. BsmI polymorphisms in vitamin D receptor gene are associated with diabetic nephropathy in type 2 diabetes in the Han Chinese population. Gene. 2012;495:183–188. [PubMed]
85. Lozano-Maneiro L., Puente-Garcia A. Renin-angiotensin-aldosterone system blockade in diabetic nephropathy. Present evidences. J Clin Med. 2015;4:1908–1937. [PubMed]
86. Wada T., Ohshima S., Fujisawa E. Aldosterone inhibits insulin-induced glucose uptake by degradation of insulin receptor substrate (IRS) 1 and IRS2 via a reactive oxygen species-mediated pathway in 3T3-L1 adipocytes. Endocrinology. 2009;150:1662–1669. [PubMed]
87. Hirata A., Maeda N., Nakatsuji H. Contribution of glucocorticoid-mineralocorticoid receptor pathway on the obesity-related adipocyte dysfunction. Biochem Biophys Res Commun. 2012;419:182–187. [PubMed]
88. Waanders F., Visser F.W., Gans R.O. Current concepts in the management of diabetic nephropathy. Neth J Med. 2013;71:448–458. [PubMed]
89. Li Z., Zhang L., Shi W. Spironolactone inhibits podocyte motility via decreasing integrin beta1 and increasing integrin beta3 in podocytes under high-glucose conditions. Mol Med Rep. 2015;12:6849–6854. [PubMed]
90. Aguilar C., Rodriguez-Delfin L. Effects of spironolactone administration on the podocytes loss and progression of experimental diabetic nephropathy. Rev Peru Med Exp Salud Publica. 2012;29:490–497. [PubMed]
91. Toyonaga J., Tsuruya K., Ikeda H. Spironolactone inhibits hyperglycemia-induced podocyte injury by attenuating ROS production. Nephrol Dial Transplant. 2011;26:2475–2484. [PubMed]
92. Schjoedt K.J. The renin-angiotensin-aldosterone system and its blockade in diabetic nephropathy: main focus on the role of aldosterone. Dan Med Bull. 2011;58:B4265. [PubMed]
93. Banki N.F., Ver A., Wagner L.J. Aldosterone antagonists in monotherapy are protective against streptozotocin-induced diabetic nephropathy in rats. PLoS One. 2012;7:e39938. [PubMed]
94. Kuiper G.G., Shughrue P.J., Merchenthaler I., Gustafsson J.A. The estrogen receptor beta subtype: a novel mediator of estrogen action in neuroendocrine systems. Front Neuroendocrinol. 1998;19:253–286. [PubMed]
95. Hultcrantz M., Simonoska R., Stenberg A.E. Estrogen and hearing: a summary of recent investigations. Acta Otolaryngol. 2006;126:10–14. [PubMed]
96. Nilsson S., Makela S., Treuter E. Mechanisms of estrogen action. Physiol Rev. 2001;81:1535–1565. [PubMed]
97. Iliescu R., Reckelhoff J.F. Sex and the kidney. Hypertension. 2008;51:1000–1001. [PubMed]
98. Silbiger S., Neugarten J. Gender and human chronic renal disease. Gend Med. 2008;5(suppl A):S3–S10. [PubMed]
99. Yanes L.L., Sartori-Valinotti J.C., Reckelhoff J.F. Sex steroids and renal disease: lessons from animal studies. Hypertension. 2008;51:976–981. [PubMed]
100. Maric C. Sex, diabetes and the kidney. Am J Physiol Renal Physiol. 2009;296:F680–F688. [PubMed]
101. Maric C., Sullivan S. Estrogens and the diabetic kidney. Gend Med. 2008;5(suppl A):S103–S113. [PubMed]
102. Hovind P., Tarnow L., Parving H.H. Remission and regression of diabetic nephropathy. Curr Hypertens Rep. 2004;6:377–382. [PubMed]
103. Jacobsen P., Rossing K., Tarnow L. Progression of diabetic nephropathy in normotensive type 1 diabetic patients. Kidney Int Suppl. 1999;71:S101–S105. [PubMed]
104. Jones C.A., Krolewski A.S., Rogus J. Epidemic of end-stage renal disease in people with diabetes in the United States population: do we know the cause? Kidney Int. 2005;67:1684–1691. [PubMed]
105. Ruggenenti P., Gambara V., Perna A. The nephropathy of non-insulin-dependent diabetes: predictors of outcome relative to diverse patterns of renal injury. J Am Soc Nephrol. 1998;9:2336–2343. [PubMed]
106. Sibley S.D., Thomas W., de Boer I. Gender and elevated albumin excretion in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) cohort: role of central obesity. Am J Kidney Dis. 2006;47:223–232. [PubMed]
107. Mangili R., Deferrari G., Di Mario U. Arterial hypertension and microalbuminuria in IDDM: the Italian Microalbuminuria Study. Diabetologia. 1994;37:1015–1024. [PubMed]
108. Raile K., Galler A., Hofer S. Diabetic nephropathy in 27,805 children, adolescents, and adults with type 1 diabetes: effect of diabetes duration, A1C, hypertension, dyslipidemia, diabetes onset, and sex. Diabetes Care. 2007;30:2523–2528. [PubMed]
109. Holl R.W., Grabert M., Thon A. Urinary excretion of albumin in adolescents with type 1 diabetes: persistent versus intermittent microalbuminuria and relationship to duration of diabetes, sex, and metabolic control. Diabetes Care. 1999;22:1555–1560. [PubMed]
110. Laron-Kenet T., Shamis I., Weitzman S. Mortality of patients with childhood onset (0-17 years) type I diabetes in Israel: a population-based study. Diabetologia. 2001;44(suppl 3):B81–B86. [PubMed]
111. Orchard T.J., Dorman J.S., Maser R.E. Prevalence of complications in IDDM by sex and duration. Pittsburgh Epidemiology of Diabetes Complications Study II. Diabetes. 1990;39:1116–1124. [PubMed]
112. Schultz C.J., Konopelska-Bahu T., Dalton R.N. Microalbuminuria prevalence varies with age, sex, and puberty in children with type 1 diabetes followed from diagnosis in a longitudinal study. Oxford Regional Prospective Study Group. Diabetes Care. 1999;22:495–502. [PubMed]
113. Breyer J.A., Bain R.P., Evans J.K. Predictors of the progression of renal insufficiency in patients with insulin-dependent diabetes and overt diabetic nephropathy. The Collaborative Study Group. Kidney Int. 1996;50:1651–1658. [PubMed]
114. Monti M.C., Lonsdale J.T., Montomoli C. Familial risk factors for microvascular complications and differential male-female risk in a large cohort of American families with type 1 diabetes. J Clin Endocrinol Metab. 2007;92:4650–4655. [PubMed]
115. Rossing P., Hougaard P., Parving H.H. Risk factors for development of incipient and overt diabetic nephropathy in type 1 diabetic patients: a 10-year prospective observational study. Diabetes Care. 2002;25:859–864. [PubMed]
116. Hodges-Gallagher L., Valentine C.D., El Bader S., Kushner P.J. Estrogen receptor beta increases the efficacy of antiestrogens by effects on apoptosis and cell cycling in breast cancer cells. Breast Cancer Res Treat. 2008;109:241–250. [PubMed]
117. Doublier S., Lupia E., Catanuto P., Elliot S.J. Estrogens and progression of diabetic kidney damage. Curr Diabetes Rev. 2011;7:28–34. [PubMed]
118. Goldfarb S., Ziyadeh F.N. TGF-beta: a crucial component of the pathogenesis of diabetic nephropathy. Trans Am Clin Climatol Assoc. 2001;112:27–32. [discussion: 33] [PubMed]
119. Yamamoto T., Nakamura T., Noble N.A. Expression of transforming growth factor beta is elevated in human and experimental diabetic nephropathy. Proc Natl Acad Sci USA. 1993;90:1814–1818. [PubMed]
120. Yamamoto T., Noble N.A., Cohen A.H. Expression of transforming growth factor-beta isoforms in human glomerular diseases. Kidney Int. 1996;49:461–469. [PubMed]
121. Ziyadeh F.N. Mediators of diabetic renal disease: the case for tgf-Beta as the major mediator. J Am Soc Nephrol. 2004;15(suppl 1):S55–S57. [PubMed]
122. Mankhey R.W., Bhatti F., Maric C. 17beta-Estradiol replacement improves renal function and pathology associated with diabetic nephropathy. Am J Physiol Renal Physiol. 2005;288:F399–F405. [PubMed]
123. Mankhey R.W., Wells C.C., Bhatti F., Maric C. 17beta-Estradiol supplementation reduces tubulointerstitial fibrosis by increasing MMP activity in the diabetic kidney. Am J Physiol Regul Integr Comp Physiol. 2007;292:R769–R777. [PubMed]
124. Chin M., Isono M., Isshiki K. Estrogen and raloxifene, a selective estrogen receptor modulator, ameliorate renal damage in db/db mice. Am J Pathol. 2005;166:1629–1636. [PubMed]
125. von Hertzen L., Forsblom C., Stumpf K. Highly elevated serum phyto-oestrogen concentrations in patients with diabetic nephropathy. J Intern Med. 2004;255:602–609. [PubMed]
126. Chen W., Howell M.L., Li Y. Vitamin A and feeding statuses modulate the insulin-regulated gene expression in Zucker lean and fatty primary rat hepatocytes. PLoS One. 2014;9:e100868. [PubMed]
127. Zhang R., Wang Y., Li R., Chen G. Transcriptional factors mediating retinoic acid signals in the control of energy metabolism. Int J Mol Sci. 2015;16:14210–14244. [PubMed]
128. Kastner P., Mark M., Chambon P. Nonsteroid nuclear receptors: what are genetic studies telling us about their role in real life? Cell. 1995;83:859–869. [PubMed]
129. Mangelsdorf D.J., Evans R.M. The RXR heterodimers and orphan receptors. Cell. 1995;83:841–850. [PubMed]
130. Mohler M.L., He Y., Wu Z. Recent and emerging anti-diabetes targets. Med Res Rev. 2009;29:125–195. [PubMed]
131. Zhang H., Xu X., Chen L. Molecular determinants of magnolol targeting both RXRα and PPARγ PLoS One. 2011;6:e28253. [PubMed]
132. Brtko J., Dvorak Z. Triorganotin compounds—ligands for “rexinoid” inducible transcription factors: biological effects. Toxicol Lett. 2015;234:50–58. [PubMed]
133. Blumberg B., Evans R.M. Orphan nuclear receptors—new ligands and new possibilities. Genes Dev. 1998;12:3149–3155. [PubMed]
134. Mangelsdorf D.J., Ong E.S., Dyck J.A., Evans R.M. Nuclear receptor that identifies a novel retinoic acid response pathway. Nature. 1990;345:224–229. [PubMed]
135. Mangelsdorf D.J., Borgmeyer U., Heyman R.A. Characterization of three RXR genes that mediate the action of 9-cis retinoic acid. Genes Dev. 1992;6:329–344. [PubMed]
136. Dolle P., Fraulob V., Kastner P., Chambon P. Developmental expression of murine retinoid X receptor (RXR) genes. Mech Dev. 1994;45:91–104. [PubMed]
137. Chai D., Wang B., Shen L. RXR agonists inhibit high-glucose-induced oxidative stress by repressing PKC activity in human endothelial cells. Free Radic Biol Med. 2008;44:1334–1347. [PubMed]
138. Hsieh C.H., Liang K.H., Hung Y.J. Analysis of epistasis for diabetic nephropathy among type 2 diabetic patients. Hum Mol Genet. 2006;15:2701–2708. [PubMed]
139. Watt A.J., Garrison W.D., Duncan S.A. HNF4: a central regulator of hepatocyte differentiation and function. Hepatology. 2003;37:1249–1253. [PubMed]
140. Mohlke K.L., Boehnke M. The role of HNF4A variants in the risk of type 2 diabetes. Curr Diab Rep. 2005;5:149–156. [PubMed]
141. Niehof M., Borlak J. HNF4 alpha and the Ca-channel TRPC1 are novel disease candidate genes in diabetic nephropathy. Diabetes. 2008;57:1069–1077. [PubMed]
142. Wang Y., Chaudhari S., Ren Y., Ma R. Impairment of hepatic nuclear factor-4α binding to the Stim1 promoter contributes to high glucose-induced upregulation of STIM1 expression in glomerular mesangial cells. Am J Physiol Renal Physiol. 2015;308:F1135–F1145. [PubMed]
143. Liou J., Kim M.L., Heo W.D. STIM is a Ca2+ sensor essential for Ca2+-store-depletion-triggered Ca2+ influx. Curr Biol. 2005;15:1235–1241. [PubMed]
144. Roos J., DiGregorio P.J., Yeromin A.V. STIM1, an essential and conserved component of store-operated Ca2+ channel function. J Cell Biol. 2005;169:435–445. [PubMed]
145. Mendel D.B., Crabtree G.R. HNF-1, a member of a novel class of dimerizing homeodomain proteins. J Biol Chem. 1991;266:677–680. [PubMed]
146. Yamagata K., Oda N., Kaisaki P.J. Mutations in the hepatocyte nuclear factor-1alpha gene in maturity-onset diabetes of the young (MODY3) Nature. 1996;384:455–458. [PubMed]
147. Byrne M.M., Sturis J., Menzel S. Altered insulin secretory responses to glucose in diabetic and nondiabetic subjects with mutations in the diabetes susceptibility gene MODY3 on chromosome 12. Diabetes. 1996;45:1503–1510. [PubMed]
148. So W.Y., Ng M.C., Horikawa Y. Genetic variants of hepatocyte nuclear factor-1beta in Chinese young-onset diabetic patients with nephropathy. J Diabetes Complications. 2003;17:369–373. [PubMed]
149. Ismail-Beigi F., Craven T., Banerji M.A. Effect of intensive treatment of hyperglycaemia on microvascular outcomes in type 2 diabetes: an analysis of the ACCORD randomised trial. Lancet. 2010;376:419–430. [PubMed]
150. Keech A., Simes R.J., Barter P. Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial. Lancet. 2005;366:1849–1861. [PubMed]
151. Polvani S., Tarocchi M., Tempesti S. Peroxisome proliferator activated receptors at the crossroad of obesity, diabetes, and pancreatic cancer. World J Gastroenterol. 2016;22:2441–2459. [PubMed]
152. Askari B., Wietecha T., Hudkins K.L. Effects of CP-900691, a novel peroxisome proliferator-activated receptor alpha, agonist on diabetic nephropathy in the BTBR ob/ob mouse. Lab Invest. 2014;94:851–862. [PubMed]
153. Feng Y.H., Fu P. Dual blockade of the renin-angiotensin-aldosterone system in type 2 diabetic kidney disease. Chin Med J (Engl) 2016;129:81–87. [PubMed]
154. Kumar R., Schaefer J., Grande J.P., Roche P.C. Immunolocalization of calcitriol receptor, 24-hydroxylase cytochrome P-450, and calbindin D28k in human kidney. Am J Physiol. 1994;266:F477–F485. [PubMed]
155. Zhang Z., Yuan W., Sun L. 1,25-Dihydroxyvitamin D3 targeting of NF-kappaB suppresses high glucose-induced MCP-1 expression in mesangial cells. Kidney Int. 2007;72:193–201. [PubMed]
156. Wang Y., Zhou J., Minto A.W. Altered vitamin D metabolism in type II diabetic mouse glomeruli may provide protection from diabetic nephropathy. Kidney Int. 2006;70:882–891. [PubMed]
157. Neugarten J., Acharya A., Lei J., Silbiger S. Selective estrogen receptor modulators suppress mesangial cell collagen synthesis. Am J Physiol Renal Physiol. 2000;279:F309–F318. [PubMed]
158. Potier M., Karl M., Zheng F. Estrogen-related abnormalities in glomerulosclerosis-prone mice: reduced mesangial cell estrogen receptor expression and prosclerotic response to estrogens. Am J Pathol. 2002;160:1877–1885. [PubMed]
159. Bhat H.K., Hacker H.J., Bannasch P. Localization of estrogen receptors in interstitial cells of hamster kidney and in estradiol-induced renal tumors as evidence of the mesenchymal origin of this neoplasm. Cancer Res. 1993;53:5447–5451. [PubMed]

Articles from Kidney International Reports are provided here courtesy of Elsevier