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1.  Adiponectin effects on the kidney 
Adiponectin is a 30-kDa polypeptide secreted primarily by adipose tissue and plays a key role in kidney disease. In obesity, reduced adiponectin levels are associated with insulin resistance, cardiovascular disease and obesity related kidney disease. The latter includes microalbuminuria, glomerulomegaly, overt proteinuria and focal segmental glomerulosclerosis. Adiponectin levels in type 2 diabetics also negatively correlate with early features of nephropathy. However, in patients with established chronic kidney disease, adiponectin levels are elevated and positively predict progression of disease. The mechanism of action of adiponectin in the kidney appears to be related to AMPK activation and NADPH oxidase. Further studies are needed to elucidate this pathway and investigate the role of potential targets of adiponectin-AMPK-Nox pathway for CKD as obesity-related CKD is increasing worldwide.
PMCID: PMC4252567  PMID: 24417947
obesity; kidney disease; adiponectin; adipokines; proteinuria; albuminuria; AMP-activated protein kinase; oxidant stress
2.  Obesity, oxidative stress, and fibrosis in chronic kidney disease 
Kidney International Supplements  2014;4(1):113-117.
Obesity in combination with diabetes and hypertension likely is contributing to the increasing incidence of chronic kidney disease (CKD) in the 21st century worldwide and requires novel insights and strategies for treatment. There is an increasing recognition that the kidney has an important role in the complex inter-organ communication that occurs with the development of inflammation and fibrosis with obesity. Inhibition of the adiponectin-AMPK pathway has now become established as a critical pathway regulating both inflammation and pro-fibrotic pathways for both obesity-related kidney disease and diabetic kidney disease. AMPK regulates NFκB activation and is a potent regulator of NADPH oxidases. Nox4 in particular has emerged as a key contribtor to the early inflammation of diabetic kidney disease. AMPK also regulates several transcription factors that contribute to stimulation of the transforming growth factor-beta (TGF-β) system. Another key aspect of AMPK regulation is its control of mammalian target of rapamycin (mTOR) and mitochondrial biogenesis. Inhibition of PGC-1α, the transcriptional co-activator of mitochondrial biogenesis is being recognized as a key pathway that is inhibited in diabetic kidney disease and may be linked to inhibition of mitochondrial function. Translation of this concept is emerging via the field of urine metabolomics, as several metabolites linked to mitochondria are consistently downregulated in human diabetic kidney disease. Further studies to explore the role of AMPK and related energy-sensing pathways will likely lead to a more comprehensive understanding of why the kidney is affected early on and in a progressive manner with obesity and diabetes.
PMCID: PMC4220515  PMID: 25401040
adiponectin; AMPK; inflammation; NADPH oxidase; USF1
3.  Autophagy and metabolic changes in obesity-related chronic kidney disease 
Nephrology Dialysis Transplantation  2013;28(Suppl 4):iv29-iv36.
Obesity is a long-term source of cellular stress that predisposes to chronic kidney disease (CKD). Autophagy is a homeostatic mechanism for cellular quality control through the disposal and recycling of cellular components. During times of cellular stress, autophagy affords mechanisms to manage stress by selectively ridding the cell of the accumulation of potentially toxic proteins, lipids and organelles. The adaptive processes employed may vary between cell types and selectively adjust to the insult by inducing components of the basic autophagy machinery utilized by the cells while not under duress. In this review, we will discuss the autophagic responses of organs to cellular stressors, such as high-fat diet, obesity and diabetes, and how these mechanisms may prevent or promote the progression of disease. The identification of early cellular mechanisms in the advent of obesity- and diabetes-related renal complications could afford avenues for future therapeutic interventions.
PMCID: PMC3814227  PMID: 23901047
AMPK; diabetes; high fat diet; insulin resistance; mTOR
4.  Adipokines protecting CKD 
Nephrology Dialysis Transplantation  2013;28(Suppl 4):iv15-iv22.
Increasing incidence of chronic kidney disease (CKD) which leads to end-stage renal disease (ESRD) is one of the major health issues in the modern world and requires novel strategies for treatment. Adipose tissue has been recognized to have endocrine function and secretes a variety of hormones called adipokines. Several adipokines have been implicated in the pathogenesis of CKD and may have a strong impact as a risk factor for renal decline. The aim of this review is to provide an overview of the role of adipokines in the progression of CKD, with focus on recent experimental and clinical advances.
PMCID: PMC3814228  PMID: 24179009
adipokine; adiponectin; AMPK; CKD; USF-1
5.  Antifibrotic Treatment and Other New Strategies for Improving Renal Outcomes 
Contributions to nephrology  2011;170:217-227.
Diabetic nephropathy (DN) is clinically characterized by proteinuria and hypertension. Investigations suggest that matrix accumulation and inflammatory processes contribute to the pathological features of this progressive disease. This chapter reviews novel targeted approaches to the treatment of DN, with the goal of slowing the progression and improving renal function. Many studies support the use of agents that block the renin-angiotensin-aldosterone system in DN. Novel, oral agents that are promising in early clinical studies are agents such as pirfenidone and bardoxolone as they are associated with early improvement in renal function in patients with advanced diabetic kidney disease. Additionally, strategies that inhibit inflammatory cytokines, chemokines, adhesion molecules and mediators of the innate immune response may provide novel targets for the treatment of DN. Larger clinical studies are eagerly awaited to determine if new agents that specifically block kidney fibrosis and inflammation will delay, arrest and possibly reverse progressive renal failure.
PMCID: PMC4124634  PMID: 21659774
6.  Mouse Models of Diabetic Nephropathy 
Diabetic nephropathy is the major cause of end-stage renal disease worldwide. Despite its prevalence, identification of specific factors that cause or predict diabetic nephropathy has been delayed in part by lack of reliable animal models that mimic the disease in humans. The Animal Models of Diabetic Complications Consortium (AMDCC) was created 8 years ago by the National Institutes of Health to develop and characterize models of diabetic nephropathy and other complications. This interim report details the progress made toward that goal, specifically in the development and testing of murine models. Updates are provided on validation criteria for early and advanced diabetic nephropathy, phenotyping methods, the effect of background strain on nephropathy, current best models of diabetic nephropathy, negative models and views of future directions. AMDCC investigators and other investigators in the field have yet to validate a complete murine model of human diabetic kidney disease. Nonetheless, the critical analysis of existing murine models substantially enhances our understanding of this disease process.
PMCID: PMC4075053  PMID: 19729434
7.  Visualizing the podocyte with multiphoton microscopy 
The podocyte is a highly specialized kidney glomerular epithelial cell that plays an essential role in glomerular filtration and is believed to be the target of numerous glomerular diseases leading to proteinuria. Despite the leaps in our understanding of podocyte biology, new methodologies are needed to facilitate research into the cell. Multiphoton microscopy (MPM) was used to image the nephrin knockout/green fluorescent protein (GFP) knock-in heterozygote (Nphs1tm1Rkl/J) mouse. The nephrin promoter restricts GFP expression to the podocytes that fluoresce green under excitation. From the exterior of an intact kidney, MPM can peer into the renal parenchyma and visualize the podocytes that outline the globular shape of the glomeruli. Details as fine as the podocyte’s secondary processes can be resolved. In contrast, podocytes exhibit no fluorescence in the wildtype mouse and are invisible to MPM. Phenotypically, there are no significant differences between wildtype and Nphs1tm1Rkl/J mice in body weight, urinary albumin excretion, creatinine clearance, or glomerular depth. Interestingly, the glomeruli are closer to the kidney capsule in female mice, making the gender the preferred choice for MPM. For the first time, green fluorescent podocytes in a mouse model free of confounding phenotypes can be visualized unequivocally and in the “positive” by MPM, facilitating intravital studies of the podocyte.
PMCID: PMC3518538  PMID: 23022193
green fluorescent protein; 2-photon microscopy; podocyte processes; renal corpuscle
8.  AMPK dysregulation promotes diabetes-related reduction of superoxide and mitochondrial function 
The Journal of Clinical Investigation  2013;123(11):4888-4899.
Diabetic microvascular complications have been considered to be mediated by a glucose-driven increase in mitochondrial superoxide anion production. Here, we report that superoxide production was reduced in the kidneys of a steptozotocin-induced mouse model of type 1 diabetes, as assessed by in vivo real-time transcutaneous fluorescence, confocal microscopy, and electron paramagnetic resonance analysis. Reduction of mitochondrial biogenesis and phosphorylation of pyruvate dehydrogenase (PDH) were observed in kidneys from diabetic mice. These observations were consistent with an overall reduction of mitochondrial glucose oxidation. Activity of AMPK, the major energy-sensing enzyme, was reduced in kidneys from both diabetic mice and humans. Mitochondrial biogenesis, PDH activity, and mitochondrial complex activity were rescued by treatment with the AMPK activator 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR). AICAR treatment induced superoxide production and was linked with glomerular matrix and albuminuria reduction in the diabetic kidney. Furthermore, diabetic heterozygous superoxide dismutase 2 (Sod2+/–) mice had no evidence of increased renal disease, and Ampka2–/– mice had increased albuminuria that was not reduced with AICAR treatment. Reduction of mitochondrial superoxide production with rotenone was sufficient to reduce AMPK phosphorylation in mouse kidneys. Taken together, these results demonstrate that diabetic kidneys have reduced superoxide and mitochondrial biogenesis and activation of AMPK enhances superoxide production and mitochondrial function while reducing disease activity.
PMCID: PMC3809777  PMID: 24135141
9.  In vivo validation and 3D visualization of broadband ultrasound molecular imaging 
Ultrasound can selectively and specifically visualize upregulated vascular receptors through the detection of bound microbubbles. However, most current ultrasound molecular imaging methods incur delays that result in longer acquisition times and reduced frame rates. These delays occur for two main reasons: 1) multi-pulse imaging techniques are used to differentiate microbubbles from tissue and 2) acquisition occurs after free bubble clearance (>6 minutes) in order to differentiate bound from freely circulating microbubbles. In this paper, we validate tumor imaging with a broadband single pulse molecular imaging method that is faster than the multi-pulse methods typically implemented on commercial scanners. We also combine the single pulse method with interframe filtering to selectively image targeted microbubbles without waiting for unbound bubble clearance, thereby reducing acquisition time from 10 to 2 minutes. The single pulse imaging method leverages non-linear bubble behavior by transmitting at low and receiving at high frequencies (TLRH). We implemented TLRH imaging and visualized the accumulation of intravenously administrated integrin-targeted microbubbles in a phantom and a Met-1 mouse tumor model. We found that the TLRH contrast imaging has a ~2-fold resolution improvement over standard contrast pulse sequencing (CPS) imaging. By using interframe filtering, the tumor contrast was 24.8±1.6 dB higher after the injection of integrin-targeted microbubbles than non-targeted control MBs, while echoes from regions lacking the target integrin were suppressed by 26.2±2.1 dB as compared with tumor echoes. Since real-time three-dimensional (3D) molecular imaging provides a more comprehensive view of receptor distribution, we generated 3D images of tumors to estimate their volume, and these measurements correlated well with expected tumor sizes. We conclude that TLRH combined with interframe filtering is a feasible method for 3D targeted ultrasound imaging that is faster than current multi-pulse strategies.
PMCID: PMC3715778  PMID: 23901359
Targeted microbubbles; ultrasound molecular imaging; angiogenesis; 3D visualization
10.  Sugar, Sex, and TGF-β in Diabetic Nephropathy 
Seminars in nephrology  2012;32(3):261-268.
TGF-β is well known to play a critical role in diabetic kidney disease, and ongoing clinical studies are testing the potential therapeutic promise of inhibiting TGF-β production and action. An aspect of TGF-β action that has not received much attention is its potential role in explaining sex-related proclivity for kidney disease. In this review, we discuss recent studies linking TGF-β signaling to sex-related effects in diabetic kidney disease and suggest targets for future studies.
PMCID: PMC3442601  PMID: 22835457
Sex difference; kidney; diabetes
11.  Mannan-Binding Lectin in Diabetic Kidney Disease: The Impact of Mouse Genetics in a Type 1 Diabetes Model 
Experimental Diabetes Research  2012;2012:678381.
Background. Mannan-binding lectin (MBL) is involved in the development of diabetic nephropathy. MBL is a part of the innate immune system where it can activate the complement system. Serum MBL level predicts later renal impairment in diabetes patients. Direct involvement of MBL in the development of diabetic kidney disease is observed in one animal strain. However, this involvement may differ among the animal strains. We thus examined the impact of the genetic background on the role of MBL in diabetic nephropathy. Materials/Methods. C57BL/6JBomTac and 129S6/SvEvTac mice were compared. In both strains, experimental type 1 diabetes was induced in wild-type (WT) and MBL-knockout (MBL-KO) mice by streptozotocin. Nondiabetic WT and MBL-KO mice were used as controls. We tested if MBL modified the diabetes-induced kidney changes by two-way ANOVA allowing for interaction. Results. MBL aggravated diabetes-induced kidney growth and glomerulus enlargement in C57BL/6JBomTac mice. MBL did not modify diabetes effects on glomerular basement membrane thickness or mesangial volume in any strain. Diabetes-induced changes in renal gene transcription of growth factors and matrix components were unaffected by MBL. Conclusions. Strain-specific MBL effects were found on downstream diabetic kidney changes. This emphasizes the importance of genetic background in this model of diabetic complications.
PMCID: PMC3356895  PMID: 22645604
12.  Targeted Renal Therapies through Microbubbles and Ultrasound 
Advanced drug delivery reviews  2010;62(14):1369-1377.
Microbubbles and ultrasound enhance the cellular uptake of drugs (including gene constructs) into the kidney. Microbubble induced modifications to the size selectivity of the filtration capacity of the kidney may enable drugs to enter previously inaccessible compartments of the kidney. So far, negative renal side-effects such as capillary bleeding have been reported only in rats, with no apparent damage in larger models such as pigs and rabbits.
Although local delivery is accomplished by applying ultrasound only to the target area, efficient delivery using conventional microbubbles has depended on the combined injection of both drugs and microbubbles directly into the renal artery. Conjugation of antibodies to the shell of microbubbles allows for the specific accumulation of microbubbles in the target tissue after intravenous injection. This exciting approach opens new possibilities for both drug delivery and diagnostic ultrasound imaging in the kidney.
PMCID: PMC2992851  PMID: 20946925
Microbubbles; Ultrasound; Kidney; Drug delivery; Bioeffects; Contrast agents; Molecular imaging; Targeted microbubbles
13.  Role of Reactive Oxygen Species in Hyper-Adrenergic Hypertension: Biochemical, Physiological, and Pharmacological Evidence from Targeted Ablation of the Chromogranin A (Chga) Gene 
Oxidative stress, an excessive production of reactive oxygen species (ROS) outstripping antioxidant defense mechanisms, occurs in cardiovascular pathologies including hypertension. Here, we used biochemical, physiological, and pharmacological approaches to explore the role of derangements of catecholamines, ROS, and NO• in the development of a hyper-adrenergic model of hereditary hypertension: targeted ablation (knockout, KO) of chromogranin A (Chga) in the mouse.
Methods and Results
Homozygous (−/−) Chga gene knockout (KO) mice were compared to wild-type (WT, +/+) controls. In the KO mouse, elevations of systolic and diastolic BP were accompanied by not only elevated catecholamine (norepinephrine and epinephrine) concentrations, but also increased ROS (H2O2) and isoprostane (an index of lipid peroxidation), as well as depletion of NO•. Renal transcript analyses implicated changes in Nox1/2, Xo/Xdh, and Sod1,2 mRNAs in ROS elevation by the KO state. KO alterations in BP, catecholamines, H2O2, isoprostane, and NO• could be abrogated or even normalized (rescued) by either sympathetic outflow inhibition (with clonidine) or NADPH oxidase inhibition (with apocynin). In cultured renal podocytes, H2O2 production was substantially augmented by epinephrine (likely through b2-adrenergic receptors) and modestly diminished by norepinephrine (likely through a1-adrenergic receptors).
ROS seem to play a necessary role in the development of hyper-adrenergic hypertension in this model, in a process mechanistically linking elevated BP with catecholamine excess, renal transcriptional responses, ROS elevation, lipid peroxidation, and NO• depletion. Some of the changes seem to be dependent on transcription, while others are immediate. The cycle could be disrupted by inhibition of either sympathetic outflow or NADPH oxidase. Since common genetic variation at the human CHGA locus alters BP, the results have implications for antihypertensive treatment as well as prevention of target-organ consequences of the disease. The results document novel pathophysiological links between the adrenergic system andc oxidative stress, and suggest new strategies to probe the role and actions of ROS within this setting.
PMCID: PMC3052689  PMID: 20729505
Chromogranin A; hypertension; reactive oxygen species; nitric oxide
14.  The Role of Aldosteronism in Causing Obesity-Related Cardiovascular Risk 
Cardiology clinics  2010;28(3):517-527.
A large body of evidence strongly links aldosterone to development and progression of cardiovacscular disease, including vascular stiffness, left ventricular hypertrophy, congestive heart failure, chronic kidney disease, and especially, hypertension. Emerging data suggests that adipocytes may serve as a source of aldosterone, either directly, or indirectly, through release of aldosterone-stimulating factors. If adipocytes are confirmed to contribute importantly to hyperaldosteronism, it would have significant clinical implications in linking aldosterone to obesity-related increases in cardiovascular risk. Such a cause-and-effect would then provide the opportunity to reverse that risk with preferential use of aldosterone antagonists in obese patients.
PMCID: PMC2904339  PMID: 20621254
aldosterone; obesity; hypertension; adipocyte; spironolactone; eplerenone
15.  Fisetin Lowers Methylglyoxal Dependent Protein Glycation and Limits the Complications of Diabetes 
PLoS ONE  2011;6(6):e21226.
The elevated glycation of macromolecules by the reactive dicarbonyl and α-oxoaldehyde methylglyoxal (MG) has been associated with diabetes and its complications. We have identified a rare flavone, fisetin, which increases the level and activity of glyoxalase 1, the enzyme required for the removal of MG, as well as the synthesis of its essential co-factor, glutathione. It is shown that fisetin reduces two major complications of diabetes in Akita mice, a model of type 1 diabetes. Although fisetin had no effect on the elevation of blood sugar, it reduced kidney hypertrophy and albuminuria and maintained normal levels of locomotion in the open field test. This correlated with a reduction in proteins glycated by MG in the blood, kidney and brain of fisetin-treated animals along with an increase in glyoxalase 1 enzyme activity and an elevation in the expression of the rate-limiting enzyme for the synthesis of glutathione, a co-factor for glyoxalase 1. The expression of the receptor for advanced glycation end products (RAGE), serum amyloid A and serum C-reactive protein, markers of protein oxidation, glycation and inflammation, were also increased in diabetic Akita mice and reduced by fisetin. It is concluded that fisetin lowers the elevation of MG-protein glycation that is associated with diabetes and ameliorates multiple complications of the disease. Therefore, fisetin or a synthetic derivative may have potential therapeutic use for the treatment of diabetic complications.
PMCID: PMC3124487  PMID: 21738623
16.  Sulodexide ameliorates early but not late kidney disease in models of radiation nephropathy and diabetic nephropathy 
Nephrology Dialysis Transplantation  2010;25(6):1803-1810.
Background. Sulodexide is a glycosaminoglycan with anticoagulant and antithrombotic activities. Although sulodexide reduced albuminuria in patients with type 1 and type 2 diabetes, long-term effects on chronic renal injury are not established. We investigated sulodexide effects and mechanisms in a rat radiation nephropathy model and in the db/db mouse model of diabetic kidney disease.
Methods. Sprague–Dawley rats received kidney radiation and were treated as follows: 15 mg/kg/day sulodexide s.c., 6 day/week (SUL) or no treatment (CONT). Subsets of animals were sacrificed after 8 weeks and 12 weeks. Blood pressure, serum creatinine, creatinine clearance (CrCl) and urinary protein excretion were measured every 4 weeks. Sclerosis and plasminogen activator inhibitor-1 (PAI-1) expression were assessed at 8 and 12 weeks, and collagen I, total collagen content and phospho-smad-2 expressions were determined at 12 weeks. Twelve-week-old db/db mice received sulodexide as above or vehicle. Albuminuria and CrCl were assessed at intervals till sacrifice at week 9 with assessment of urinary transforming growth factor-β (TGF-β) and glomerular lesions.
Results. Blood pressure, serum creatinine and CrCl were not different in radiation rat CONT vs SUL at any time. Proteinuria was significantly lower in SUL compared to CONT at 4 and 8 weeks but not at 12 weeks. Sclerosis and PAI-1 expression trended lower in SUL vs CONT at 8 weeks. There was no difference between the groups in sclerosis, collagen I mRNA, total collagen content or PAI-1 expression at 12 weeks. Phospho-smad 2 expression was significantly decreased in SUL compared to CONT at 12 weeks. Db/db mice with or without SUL showed no difference in urinary albumin/creatinine ratio, urine TGF-β or mesangial matrix expansion.
Conclusions. Our data show that sulodexide can reduce the early, but not late, proteinuria in radiation nephropathy in rats. In addition, sulodexide did not affect urine TGF-β established albuminuria or mesangial matrix expansion in a chronic model of diabetic kidney disease in mice. Although sulodexide may affect TGF-β activation in radiation nephropathy, this effect appeared insufficient in this model to inhibit the expressions of PAI-1 and collagen and reduce accumulation of extracellular matrix. These results may explain in part its lack of efficacy in recent clinical trials of chronic kidney disease.
PMCID: PMC2902889  PMID: 20061322
glomerulosclerosis; PAI-1; proteinuria; sulodexide; TGF-beta
17.  Ultrasound Molecular Imaging of Tumor Angiogenesis with an Integrin Targeted Microbubble Contrast Agent 
Investigative radiology  2011;46(4):215-224.
Rationale and Objectives
Ultrasound molecular imaging is an emerging technique for sensitive detection of intravascular targets. Molecular imaging of angiogenesis has strong potential for both clinical use and as a research tool in tumor biology and the development of anti-angiogenic therapies. Our objective is to develop a robust microbubble (MB) ultrasound contrast agent platform to which targeting ligands can be conjugated by biocompatible, covalent conjugation chemistry, and to develop a pure low mechanical index imaging processing method and corresponding quantifying method. The microbubbles and the imaging methods were evaluated in a mouse model of breast cancer in vivo.
Materials and Methods
We utilized a cyclic RGD (cRGD) pentapeptide containing a terminal cysteine group conjugated to the surface of MB bearing pyridyldithio-propionate (PDP) for targeting αvβ3 integrins. As negative controls, MB without a ligand or MB bearing a scrambled sequence (cRAD) were prepared. To enable characterization of peptides bound to MB surfaces, the cRGD peptide was labeled with FITC and detected by plate fluorometry, flow cytometry, and fluorescence microscopy. Targeted adhesion of cRGD-MB was demonstrated in an in vitro flow adhesion assay against recombinant murine αvβ3 integrin protein and αvβ3 integrin-expressing endothelial cells (bEnd.3). The specificity of cRGD-MB for αvβ3 integrin was demonstrated by treating bEnd.3 EC with a blocking antibody. A murine model of mammary carcinoma was used to assess targeted adhesion and ultrasound molecular imaging in vivo. The targeted microbubbles were visualized using a low mechanical index contrast imaging pulse sequence, and quantified by intensity normalization and two-dimensional Fourier transform analysis,
The cRGD ligand concentration on the MB surface was ~8.2 × 106 molecules/MB. At a wall shear stress of 1.0 dynes/cm2, cRGD-MB exhibited 5-fold higher adhesion to immobilized recombinant αvβ3 integrin relative to non-targeted MB and cRAD-MB controls. Similarly, cRGD-MB showed significantly greater adhesion to bEnd.3 EC compared to non-targeted MB and cRAD-MB. In addition, cRGD-MB, but not non-targeted MB or cRAD-MB, showed significantly enhanced contrast signals with a high tumor-to-background ratio. The adhesion of cRGD-MB to bEnd.3 was reduced by 80% after using anti-αv monoclonal antibody to treat bEnd.3. The normalized image intensity amplitude was ~0.8 seven minutes after the administration of cRGD-MB relative to the intensity amplitude at the time of injection, while the spatial variance in image intensity improved the detection of bound agents. The accumulation of cRGD- MB was blocked by pre-administration with an anti-αv blocking antibody.
The results demonstrate the functionality of a novel microbubble contrast agent covalently coupled to an RGD peptide for ultrasound molecular imaging of αvβ3 integrin and the feasibility of quantitative molecular ultrasound imaging with a low mechanical index.
PMCID: PMC3075480  PMID: 21343825
18.  Burnt-Out Diabetes: The Impact of CKD Progression on the Natural Course of Diabetes Mellitus 
Many individuals with diabetic nephropathy, the leading cause of chronic kidney disease (CKD) in the United States, progress to stage 5 of CKD and undergo maintenance dialysis treatment. Recent data indicate that in up to one-third of the diabetic dialysis patients with the presumptive diagnosis of diabetic nephropathy, glycemic control improves spontaneously with the progression of CKD, loss of residual renal function and the initiation of dialysis therapy, leading to normal to low hemoglobin A1c (<6%) and glucose levels, requiring cessation of insulin or other diabetic medications. Potential contributors to this so-called “burnt-out diabetes” include decreased renal and hepatic insulin clearance, decline in renal gluconeogenesis, deficient catecholamine release, diminished food intake due to anorexia and/or diabetic gastroparesis, protein-energy wasting with resultant weight and body fat loss, and hypoglycemic effect of dialysis treatment. Although the concept of “burnt-out diabetes” appears in sharp contradistinction to the natural history of diabetes mellitus, studying this condition and its potential causes and consequences including the role of genetic factors may lead to better understanding of the pathophysiology of metabolic syndrome and diabetes mellitus in the CKD population and in many other individuals with chronic disease states associated with wasting syndrome that can confound the natural history of diabetes.
PMCID: PMC2652655  PMID: 19121768
Diabetic nephropathy; chronic kidney disease (CKD); hemoglobin A1c; glycemic control; maintenance dialysis
19.  Resveratrol delays age-related deterioration and mimics transcriptional aspects of dietary restriction without extending lifespan 
Cell metabolism  2008;8(2):157-168.
A small molecule that safely mimics the ability of dietary restriction (DR) to delay age-related diseases in laboratory animals is greatly sought after. We and others have shown that resveratrol mimics effects of DR in lower organisms. In mice, we find that resveratrol induces gene expression patterns in multiple tissues that parallel those induced by DR and every-other-day feeding. Moreover, resveratrol-fed elderly mice show a marked reduction in signs of aging including reduced albuminuria, decreased inflammation and apoptosis in the vascular endothelium, increased aortic elasticity, greater motor coordination, reduced cataract formation, and preserved bone mineral density. However, mice fed a standard diet did not live longer when treated with resveratrol beginning at 12 months of age. Our findings indicate that resveratrol treatment has a range of beneficial effects in mice but does not increase the longevity of ad libitum-fed animals when started mid-life.
PMCID: PMC2538685  PMID: 18599363
20.  Adiponectin regulates albuminuria and podocyte function in mice 
The Journal of Clinical Investigation  2008;118(5):1645-1656.
Increased albuminuria is associated with obesity and diabetes and is a risk factor for cardiovascular and renal disease. However, the link between early albuminuria and adiposity remains unclear. To determine whether adiponectin, an adipocyte-derived hormone, is a communication signal between adipocytes and the kidney, we performed studies in a cohort of patients at high risk for diabetes and kidney disease as well as in adiponectin-knockout (Ad–/–) mice. Albuminuria had a negative correlation with plasma adiponectin in obese patients, and Ad–/– mice exhibited increased albuminuria and fusion of podocyte foot processes. In cultured podocytes, adiponectin administration was associated with increased activity of AMPK, and both adiponectin and AMPK activation reduced podocyte permeability to albumin and podocyte dysfunction, as evidenced by zona occludens–1 translocation to the membrane. These effects seemed to be caused by reduction of oxidative stress, as adiponectin and AMPK activation both reduced protein levels of the NADPH oxidase Nox4 in podocytes. Ad–/– mice treated with adiponectin exhibited normalization of albuminuria, improvement of podocyte foot process effacement, increased glomerular AMPK activation, and reduced urinary and glomerular markers of oxidant stress. These results suggest that adiponectin is a key regulator of albuminuria, likely acting through the AMPK pathway to modulate oxidant stress in podocytes.
PMCID: PMC2323186  PMID: 18431508
21.  Regulation of Transforming Growth Factor–Beta in Diabetic Nephropathy: Implications for Treatment 
Seminars in nephrology  2007;27(2):153-160.
The recognition of the drivers of matrix accumulation as a therapeutic target for diabetic nephropathy is accepted by the Nephrology and pharmaceutical community. Interventions focused around Transforming Growth Factor–beta (TGF–β) will likely be an important area of clinical investigation in the near future. Understanding the various pathways involved in stimulating TGF–β in the diabetic kidney is of paramount importance in devising strategies to combat the development and progression of diabetic nephropathy. In this review we highlight the major pathways involved in stimulating TGF–β production by elevated glucose and discuss the therapeutic implications.
PMCID: PMC1948024  PMID: 17418684
Protein Kinase C; reactive oxygen species; Upstream stimulatory factor; HETE; decorin; thrombospondin; macrophages; podocytes; glucose excursion
22.  Reactive oxygen species production via NADPH oxidase mediates TGF-β-induced cytoskeletal alterations in endothelial cells 
Cytoskeletal alterations in endothelial cells have been linked to nitric oxide generation and cell-cell interactions. Transforming growth factor (TGF)-β has been described to affect cytoskeletal rearrangement in numerous cell types; however, the underlying pathway is unclear. In the present study, we found that human umbilical vein endothelial cells (HUVEC) have marked cytoskeletal alterations with short-term TGF-β treatment resulting in filipodia formation and F-actin assembly. The cytoskeletal alterations were blocked by the novel TGF-β type I receptor/ALK5 kinase inhibitor (SB-505124) but not by the p38 kinase inhibitor (SB-203580). TGF-β also induced marked stimulation of reactive oxygen species (ROS) within 5 min of TGF-β exposure. TGF-β stimulation of ROS was mediated by the NAPDH oxidase homolog Nox4 as DPI, an inhibitor of NADPH oxidase, and dominant-negative Nox4 adenovirus blocked ROS production. Finally, inhibition of ROS with ROS scavengers or dominant-negative Nox4 blocked the TGF-β effect on cytoskeleton changes in endothelial cells. In conclusion, our studies show for the first time that TGF-β-induced ROS production in human endothelial cells is via Nox4 and that TGF-β alteration of cytoskeleton in HUVEC is mediated via a Nox4-dependent pathway.
PMCID: PMC1460011  PMID: 16159901
human umbilical vein endothelial cells; cell-cell interactions; cytoskeletal rearrangement; transforming growth factor-β
23.  Selective role for superoxide in InsP3 receptor–mediated mitochondrial dysfunction and endothelial apoptosis 
The Journal of Cell Biology  2005;170(7):1079-1090.
Reactive oxygen species (ROS) play a divergent role in both cell survival and cell death during ischemia/reperfusion (I/R) injury and associated inflammation. In this study, ROS generation by activated macrophages evoked an intracellular Ca2+ ([Ca2+]i) transient in endothelial cells that was ablated by a combination of superoxide dismutase and an anion channel blocker. [Ca2+]i store depletion, but not extracellular Ca2+ chelation, prevented [Ca2+]i elevation in response to O2.− that was inositol 1,4,5-trisphosphate (InsP3) dependent, and cells lacking the three InsP3 receptor (InsP3R) isoforms failed to display the [Ca2+]i transient. Importantly, the O2.−-triggered Ca2+ mobilization preceded a loss in mitochondrial membrane potential that was independent of other oxidants and mitochondrially derived ROS. Activation of apoptosis occurred selectively in response to O2.− and could be prevented by [Ca2+]i buffering. This study provides evidence that O2.− facilitates an InsP3R-linked apoptotic cascade and may serve a critical function in I/R injury and inflammation.
PMCID: PMC2171541  PMID: 16186254
24.  Multiple Metabolic Hits Converge on CD36 as Novel Mediator of Tubular Epithelial Apoptosis in Diabetic Nephropathy 
PLoS Medicine  2005;2(2):e45.
Diabetic nephropathy (DNP) is a common complication of type 1 and type 2 diabetes mellitus and the most common cause of kidney failure. While DNP manifests with albuminuria and diabetic glomerulopathy, its progression correlates best with tubular epithelial degeneration (TED) and interstitial fibrosis. However, mechanisms leading to TED in DNP remain poorly understood.
Methods and Findings
We found that expression of scavenger receptor CD36 coincided with proximal tubular epithelial cell (PTEC) apoptosis and TED specifically in human DNP. High glucose stimulated cell surface expression of CD36 in PTECs. CD36 expression was necessary and sufficient to mediate PTEC apoptosis induced by glycated albumins (AGE-BSA and CML-BSA) and free fatty acid palmitate through sequential activation of src kinase, and proapoptotic p38 MAPK and caspase 3. In contrast, paucity of expression of CD36 in PTECs in diabetic mice with diabetic glomerulopathy was associated with normal tubular epithelium and the absence of tubular apoptosis. Mouse PTECs lacked CD36 and were resistant to AGE-BSA-induced apoptosis. Recombinant expression of CD36 in mouse PTECs conferred susceptibility to AGE-BSA-induced apoptosis.
Our findings suggest a novel role for CD36 as an essential mediator of proximal tubular apoptosis in human DNP. Because CD36 expression was induced by glucose in PTECs, and because increased CD36 mediated AGE-BSA-, CML-BSA-, and palmitate-induced PTEC apoptosis, we propose a two-step metabolic hit model for TED, a hallmark of progression in DNP.
The CD36 receptor may have a key role in the degeneration of the renal tubular epithelium, the first step in diabetic nephropathy
PMCID: PMC549593  PMID: 15737001

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