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1.  DPP4 inhibition attenuates filtration barrier injury and oxidant stress in the Zucker obese rat 
Obesity (Silver Spring, Md.)  2014;22(10):2172-2179.
Obesity-related glomerulopathy is characterized initially by glomerular hyperfiltration with hypertrophy and then development of proteinuria. Putative mechanisms include endothelial dysfunction and filtration barrier injury due to oxidant stress and immune activation. There has been recent interest in targeting dipeptidyl peptidase 4 (DPP4) enzyme due to increasing role in non-enzymatic cellular processes.
We utilized the Zucker obese (ZO) rat, (aged 8 weeks) fed a normal chow or diet containing the DPP4 inhibitor linagliptin for 8 weeks (83mg/kg rat chow).
Compared to lean controls, there were increases in plasma DPP4 activity along with proteinuria in ZO rats. ZO rats further displayed increases in glomerular size and podocyte foot process effacement. These findings occurred in parallel with decreased endothelial stromal-derived factor-1α (SDF-1α), increased oxidant markers, and tyrosine phosphorylation of nephrin and serine phosphorylation of the mammalian target of rapamycin (mTOR). DPP4 inhibition improved proteinuria along with filtration barrier remodeling, circulating and kidney tissue DPP4 activity, increased active glucagon like peptide–1 (GLP-1) as well as SDF-1α, and improved oxidant markers and the podocyte-specific protein nephrin.
These data support a role for DPP4 in glomerular filtration function and targeting DPP4 with inhibition improves oxidant stress-related glomerulopathy and associated proteinuria.
PMCID: PMC4180797  PMID: 24995775
SDF-1α; linagliptin; NADPH oxidase; DPP4 activity; obesity
2.  Synergy of antihypertensives in elderly patients with CKD 
Nature reviews. Nephrology  2012;9(1):13-15.
A recent study reports that the combination of an angiotensin-receptor blocker (ARB) and a calcium-channel blocker (versus a high-dose ARB) is associated with improved blood pressure control and reduced cardiovascular, cerebrovascular and heart failure events in an elderly chronic kidney disease population. This finding raises the possibility of using fixed-dose drug combinations to improve efficacy and compliance of antihypertensive medications.
PMCID: PMC4349578  PMID: 23183840
3.  Resistance to Insulin and Kidney Disease in the CardioRenal Metabolic Syndrome; role for Angiotensin II 
The presence of insulin resistance is increasingly recognized as an important contributor to early stage kidney disease independent of the contribution of diabetes. Important in this relationship is the strong correlation between hyperinsulinemia and low levels of albuminuria (e.g microalbuminuria). Recent work highlight mechanisms for glomerular/tubulointerstitial injury with excess insulin and emerging evidence identifies a unique role for insulin metabolic signaling and altered handling of salt reabsorption at the level of the proximal tubule. Evidence is also emerging for the role of insulin signaling in the glomerulus both epithelial and endothelial. Central to the mechanism of injury is inappropriate activation of the RAAS.
PMCID: PMC3711952  PMID: 23416840
Cardiorenal metabolic syndrome; Chronic Kidney Disease; Obesity; Insulin resistance; Hyperinsulinemia; Glomerulus; Proximal Tubule
4.  Combination Direct Renin Inhibition with Angiotensin Type 1 Receptor Blockade improves Aldosterone but does not improve Kidney Injury in the Transgenic Ren2 rat 
Regulatory Peptides  2012;176(1-3):36-44.
Enhanced renin-angiotensin-aldosterone system (RAAS) activation contributes to proteinuria and chronic kidney disease by increasing glomerular and tubulointerstitial oxidative stress, promotion of fibrosis. Renin activation is the rate limiting step in angiotensin (Ang II) and aldosterone generation, and recent work suggests direct renin inhibition improves proteinuria comparable to that seen with Ang type 1 receptor (AT1R) blockade. This is important as, even with contemporary use of AT1R blockade, the burden of kidney disease remains high. Thereby, we sought to determine if combination direct renin inhibition with AT1R blockade in vivo, via greater attenuation of kidney oxidative stress, would attenuate glomerular and proximal tubule injury to a greater extent than either intervention alone. We utilized the transgenic Ren2 rat with increased tissue RAS activity and higher serum levels of aldosterone, which manifests hypertension and proteinuria. Ren2 rats were treated with renin inhibition (aliskiren), AT1R blockade (valsartan), the combination (aliskiren+valsartan), or vehicle for 21 days. Compared to Sprague-Dawley controls, Ren2 rats displayed increased systolic pressure (SBP), circulating aldosterone, proteinuria and greater urine levels of the proximal tubule protein excretory marker beta-N-acetylglucosaminidase (β-NAG). These functional and biochemical alterations were accompanied by increases in kidney tissue NADPH oxidase subunit Rac1 and 3-nitrotyrosine (3-NT) content as well as fibronectin and collagen type III. These findings occurred in conjunction with reductions in the podocyte-specific protein podocin as well as the proximal tubule-specific megalin. Further, in transgenic animals there was increased tubulointerstitial fibrosis on light microscopy as well as ultrastructural findings of glomerular podocyte foot-process effacement and reduced tubular apical endosomal/lysosomal activity. Combination therapy led to greater reductions in SBP and serum aldosterone, but did not result in greater improvement in markers of glomerular and tubular injury (ie. β-NAG) compared to either intervention alone. Further, combination therapy did not improve markers of oxidative stress and podocyte and proximal tubule integrity in this transgenic model of RAAS-mediated kidney damage despite greater reductions in serum aldosterone and BP levels.
PMCID: PMC3348429  PMID: 22465166
Aldosterone; Combination; Renin inhibition; AT1R blockade; Podocyte; β-NAG; Oxidative Stress
5.  DPP-4 Inhibitors as Therapeutic Modulators of Immune Cell Function and Associated Cardiovascular and Renal Insulin Resistance in Obesity and Diabetes 
Cardiorenal Medicine  2013;3(1):48-56.
The prevalence of obesity and diabetes continues to rise in the United States and worldwide. These findings parallel the expansion of childhood obesity and diabetes. Obesity is a central component of the cardiorenal metabolic syndrome (CRS) which increases the risk for cardiovascular disease (CVD) and chronic kidney disease (CKD). The hallmark of obesity, CRS, and early type 2 diabetes is insulin resistance, a result of decreased insulin metabolic signaling due, in part, to enhanced serine phosphorylation and/or proteasome-mediated degradation of the insulin receptor substrate. Cardiovascular and renal insulin resistance significantly contributes to endothelial dysfunction, impaired cardiac diastolic and vascular relaxation, glomerular injury, and tubular dysfunction. In this context, multiple factors including oxidative stress, increased inflammation, and inappropriate activation of the renin-angiotensin-aldosterone and the sympathetic nervous system contribute to overweight- and obesity-induced systemic and tissue insulin resistance. One common link between obesity and the development of insulin resistance appears to be a low-grade inflammatory response resulting from dysfunctional innate and adaptive immunity. In this regard, there has been recent work on the role of dipeptidyl peptidase-4 (DPP-4) in modulating innate and adaptive immunity. The direct effects of DPP-4 on immune cells and the indirect effects through GLP-1-dependent and -independent pathways suggest effects of DPP-4 inhibition may have beneficial effects beyond glycemic control in improving CVD and renal outcomes. Accordingly, this review addresses new insights into the role of DPP-4 in immune modulation and the potential beneficial effects of DPP-4 inhibitors in insulin resistance and associated CVD and CKD prevention.
PMCID: PMC3743398  PMID: 23946724
DPP-4; Cardiorenal syndrome; Obesity; Diabetes; Insulin resistance

7.  Mineralocorticoid Receptor-Dependent Proximal Tubule Injury Is Mediated by a Redox-Sensitive mTOR/S6K1 Pathway 
American Journal of Nephrology  2011;35(1):90-100.
The mammalian target of rapamycin (mTOR) is a serine kinase that regulates phosphorylation (p) of its target ribosomal S6 kinase (S6K1), whose activation can lead to glomerular and proximal tubular cell (PTC) injury and associated proteinuria. Increased mTOR/S6K1 signaling regulates signaling pathways that target fibrosis through adherens junctions. Recent data indicate aldosterone signaling through the mineralocorticoid receptor (MR) can activate the mTOR pathway. Further, antagonism of the MR has beneficial effects on proteinuria that occur independent of hemodynamics.
Accordingly, hypertensive transgenic TG(mRen2)27 (Ren2) rats, with elevated serum aldosterone and proteinuria, and age-matched Sprague-Dawley rats were treated with either a low dose (1 mg/kg/day) or a conventional dose (30 mg/kg/day) of spironolactone (MR antagonist) or placebo for 3 weeks.
Ren2 rats displayed increases in urine levels of the PTC brush border lysosomal enzyme N-acetyl-β-aminoglycosidase (β-NAG) in conjunction with reductions in PTC megalin, the apical membrane adherens protein T-cadherin and basolateral α-(E)-catenin, and fibrosis. In concert with these abnormalities, Ren2 renal cortical tissue also displayed increased Ser2448 (p)/activation of mTOR and Thr389 (p)-S6K1 and increased 3-nitrotyrosine (3-NT) content, a marker for peroxynitrite. Low-dose spironolactone had no effect on blood pressure but decreased proteinuria and β-NAG comparable to a conventional dose of this MR antagonist. Both doses of spironolactone attenuated ultrastructural maladaptive alterations and led to comparable reductions in (p)-mTOR/(p)-S6K1, 3-NT, fibrosis, and increased expression of α-(E)-catenin, T- and N-cadherin.
Thereby, MR antagonism improves proximal tubule integrity by targeting mTOR/S6K1 signaling and redox status independent of changes in blood pressure.
PMCID: PMC3316484  PMID: 22205374
Cadherin; Megalin; β-NAG; Proteinuria
8.  The Role of Tissue Renin-Angiotensin-Aldosterone System in the Development of Endothelial Dysfunction and Arterial Stiffness 
Epidemiological studies support the notion that arterial stiffness is an independent predictor of adverse cardiovascular events contributing significantly to systolic hypertension, impaired ventricular-arterial coupling and diastolic dysfunction, impairment in myocardial oxygen supply and demand, and progression of kidney disease. Although arterial stiffness is associated with aging, it is accelerated in the presence of obesity and diabetes. The prevalence of arterial stiffness parallels the increase of obesity that is occurring in epidemic proportions and is partly driven by a sedentary life style and consumption of a high fructose, high salt, and high fat western diet. Although the underlying mechanisms and mediators of arterial stiffness are not well understood, accumulating evidence supports the role of insulin resistance and endothelial dysfunction. The local tissue renin-angiotensin-aldosterone system (RAAS) in the vascular tissue and immune cells and perivascular adipose tissue is recognized as an important element involved in endothelial dysfunction which contributes significantly to arterial stiffness. Activation of vascular RAAS is seen in humans and animal models of obesity and diabetes, and associated with enhanced oxidative stress and inflammation in the vascular tissue. The cross talk between angiotensin and aldosterone underscores the importance of mineralocorticoid receptors in modulation of insulin resistance, decreased bioavailability of nitric oxide, endothelial dysfunction, and arterial stiffness. In addition, both innate and adaptive immunity are involved in this local tissue activation of RAAS. In this review we will attempt to present a unifying mechanism of how environmental and immunological factors are involved in this local tissue RAAS activation, and the role of this process in the development of endothelial dysfunction and arterial stiffness and targeting tissue RAAS activation.
PMCID: PMC3810594  PMID: 24194732
renin-angiotensin-aldosterone system; arterial stiffness; insulin resistance; endothelial dysfunction; obesity; diabetes
9.  Angiotensin II Activation of mTOR Results in Tubulointerstitial Fibrosis through Loss of N-Cadherin 
American Journal of Nephrology  2011;34(2):115-125.
Angiotensin (Ang) II contributes to tubulointerstitial fibrosis. Recent data highlight mammalian target of rapamycin (mTOR)/S6 kinase 1 (S6K1) signaling in tubulointerstitial fibrosis; however, the mechanisms remain unclear. Thereby, we investigated the role of Ang II on mTOR/S6K1-dependent proximal tubule (PT) injury, remodeling, and fibrosis.
We utilized young transgenic Ren2 rats (R2-T) and Sprague-Dawley rats (SD-T) treated with the Ang type 1 receptor (AT1R) blocker telmisartan (2 mg · kg−1 · day−1) or vehicle (R2-C; SD-C) for 3 weeks to examine PT structure and function.
Ren2 rats displayed increased systolic blood pressure, proteinuria and increased PT oxidant stress and remodeling. There were parallel increases in kidney injury molecule-1 and reductions in neprilysin and megalin with associated ultrastructural findings of decreased clathrin-coated pits, endosomes, and vacuoles. Ren2 rats displayed increased Serine2448 phosphorylation of mTOR and downstream S6K1, in concert with ultrastructural basement membrane thickening, tubulointerstitial fibrosis and loss of the adhesion molecule N-cadherin. Telmisartan treatment attenuated proteinuria as well as the biochemical and tubulointerstitial structural abnormalities seen in the Ren2 rats.
Our observations suggest that Ang II activation of the AT1R contributes to PT brush border injury and remodeling, in part, due to enhanced mTOR/S6K1 signaling which promotes tubulointerstitial fibrosis through loss of N-cadherin.
PMCID: PMC3130895  PMID: 21720156
Angiotensin II; mTOR; N-Cadherin; Proximal tubule; Tubulointerstitial fibrosis
10.  Gestational Diabetes and the Offspring: Implications in the Development of the Cardiorenal Metabolic Syndrome in Offspring 
Cardiorenal Medicine  2012;2(2):134-142.
The risk of developing type 2 diabetes and cardiovascular disease in women who had previously been diagnosed with gestational diabetes (GDM) is well established. There is increasing evidence that the offspring of women with GDM are at increased risk for the development of all components of the cardiorenal metabolic syndrome. Overall, it appears that these offspring have an increased risk for overweight/obesity, insulin resistance, higher blood pressure, renal disease, and type 2 diabetes. However, distinct differences in regional populations, lack of routine screening and treatment of GDM worldwide, and long follow-up periods for offspring represent a challenge in assessing the risk for development of these abnormalities in the offspring of women who have had GDM.
PMCID: PMC3376343  PMID: 22851962
Gestational diabetes; Offspring; Fetal programming; Cardiorenal syndrome
11.  Prenatal Programming and Epigenetics in the Genesis of the Cardiorenal Syndrome 
Cardiorenal Medicine  2011;1(4):243-254.
The presence of a group of interacting maladaptive factors, including hypertension, insulin resistance, metabolic dyslipidemia, obesity, and microalbuminuria and/or reduced renal function, collectively constitutes the cardiorenal metabolic syndrome (CRS). Nutritional and other environmental cues during fetal development can permanently affect the composition, homeostatic systems, and functions of multiple organs and systems; this process has been referred to as ‘programming’. Since the original formulation of the notion that low birth weight is a proxy for ‘prenatal programming’ of adult hypertension and cardiovascular disease, evidence has also emerged for programming of kidney disease, insulin resistance, obesity, metabolic dyslipidemia, and other chronic diseases. The programming concept was initially predicated on the notion that in utero growth restriction due to famine was responsible for increased hypertension, and cardiovascular and renal diseases. On the other hand, we are now more commonly exposed to increasing rates of maternal obesity. The current review will discuss the overarching role of maternal overnutrition, as well as fetal undernutrition, in epigenetic programming in relation to the pathogenesis of the CRS in children and adults.
PMCID: PMC3214897  PMID: 22096456
Albuminuria; Dyslipidemia; Fetal development; Hypertension; Insulin resistance; Malnutrition; Pediatric obesity
12.  RAAS-mediated Redox effects in Chronic Kidney Disease 
The renin-angiotensin-aldosterone-system (RAAS) is central to the pathogenesis of hypertension, cardiovascular and kidney disease. Emerging evidence support various pathways through which a local renal RAAS can affect kidney function, hypertension, and cardiovascular disease. A prominent mechanism appears to be loss of redox homeostasis and formation of excessive free radicals. Free radicals such as reactive oxygen species (ROS) are necessary in normal physiologic processes including development of nephrons, erythropoeisis and tubular sodium transport. However, loss of redox homeostasis contributes to pro-inflammatory and pro-fibrotic pathways in the kidney that in turn lead to reduced vascular compliance, podocyte pathology and proteinuria. Both blockade of the RAAS and oxidative stress produces salutary effects on hypertension and glomerular filtration barrier injury. Thus, the focus of current research is on understanding the pathophysiology of chronic kidney disease in the context of an elevated RAAS and unbalanced redox mechanisms.
PMCID: PMC2680726  PMID: 19218092
Kidney; Renin; Angiotensin; Aldosterone; Redox
13.  Redox Control of Renal Function and Hypertension 
Antioxidants & Redox Signaling  2008;10(12):2047-2089.
Loss of redox homeostasis and formation of excessive free radicals play an important role in the pathogenesis of kidney disease and hypertension. Free radicals such as reactive oxygen species (ROS) are necessary in physiologic processes. However, loss of redox homeostasis contributes to proinflammatory and profibrotic pathways in the kidney, which in turn lead to reduced vascular compliance and proteinuria. The kidney is susceptible to the influence of various extracellular and intracellular cues, including the renin–angiotensin–aldosterone system (RAAS), hyperglycemia, lipid peroxidation, inflammatory cytokines, and growth factors. Redox control of kidney function is a dynamic process with reversible pro– and anti-free radical processes. The imbalance of redox homeostasis within the kidney is integral in hypertension and the progression of kidney disease. An emerging paradigm exists for renal redox contribution to hypertension. Antioxid. Redox Signal. 11, 2047–2089.
Redox Control of Cellular Function: How Is It Achieved?
Free radical contribution to redox control of hypertension
Clinical contribution to redox control of hypertension
Prooxidant enzymes and pathways
NAD(P)H oxidase
Xanthine oxidase (XO)
Lipooxygenases (LOX) and cyclooxygenases (COX)
P450 monooxygenase and mitochondrial respiratory chain enzymes (I–IV)
Antioxidant enzymes and pathways
Role of ROS in physiologic processes
Pathologic Role of ROS in Hypertension
Non–RAAS-mediated oxidative stress in hypertension
High intravascular pressure
Shear stress
High salt
Cigarette smoke
Insulin resistance/hyperinsulinemia
eNOS uncoupling
Dopaminergic system (DS)/sympathetic nervous system
Role of the RAAS in oxidative stress and hypertension
Ang II, ROS, and systemic hypertension
Ang II stimulation of NAD(P)H oxidase and hypertension
p22phox and hypertension
gp91phox (Nox2) and hypertension
p47phox and hypertension
p67phox and hypertension
p40phox and hypertension
Kidney Redox Function and Hypertension
ROS in normal kidney physiology
RAAS in the kidney
RAAS expression in developing and adult kidneys
RAAS-mediated redox mechanisms
Methods for detecting ROS in the laboratory and clinic
Nephron handling of ROS and hypertension: redox control of renal function
Redox control of kidney function
Tubuloglomerular feedback and role of ROS in macula densa
Medullary perfusion and renal hemodynamics
Pressure natriuresis
Tubular sodium transport
Renal sympathetic nerves
Nephron components and their contribution to ROS and hypertension
ROS in the glomeruli/podocytes
ROS and the glomerular basement membrane (GBM)
ROS and the mesangium
ROS and the tubule
NAD(P)H Oxidase Inhibition for the Treatment of Hypertension: Promises and Limitations
NAD(P)H oxidase–specific inhibitors
Neopterin/phenylarsine oxide
VAS2870, SI7834, and AEBSF
Monoclonal antibodies
Nonspecific NAD(P)H oxidase inhibitors
PKC inhibitors
Statins, ACE inhibitors/ARBs, and aldosterone antagonists
Future Perspectives/Conclusions
PMCID: PMC2582196  PMID: 18821850
14.  Angiotensin receptor blockers for the reduction of proteinuria in diabetic patients with overt nephropathy: results from the AMADEO study 
Diabetic kidney disease is characterized by persistent albuminuria (>300 mg/dl or >200 μg/min) that is confirmed on at least 2 occasions 3 to 6 months apart, with a progressive decline in the glomerular filtration rate (GFR), elevated arterial blood pressure, and an increased risk for cardiovascular morbidity and mortality. Diabetic kidney disease is the leading cause of end stage renal disease (ESRD) prompting investigators to evaluate mechanisms by which to slow disease progression. One such mechanism is to block the activity of angiotensin II at the receptor site and agents that follow this mechanism are referred to as angiotensin receptor blockers (ARB). There is sufficient clinical evidence to support that ARB have protective effects on kidney function in patients with diabetes and hypertension. However, in the past decade there have been few investigations comparing individual ARBs on renal outcomes. Telmisartan, a lipophilic ARB with a long half-life, has been hypothesized to have a greater anti-proteinuric effect when compared to the shorter acting losartan. Therefore, the A comparison of telMisartan versus losArtan in hypertensive type 2 DiabEtic patients with Overt nephropathy (AMADEO) trial sought to investigate renal and cardiovascular endpoints. In this review, we discuss the pathophysiology of diabetic kidney disease and implications of the AMADEO trial in the context of current understanding from recent outcome trials.
PMCID: PMC2672468  PMID: 19436679
diabetic kidney disease; hypertension; telmisartan; AMADEO
15.  Attenuation of NADPH Oxidase Activation and Glomerular Filtration Barrier Remodeling With Statin Treatment 
Hypertension  2008;51(2):474-480.
Activation of reduced nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase by angiotensin II is integral to the formation of oxidative stress in the vasculature and the kidney. 3-Hydroxy-3-methylglutaryl-coenzyme A reductase inhibition is associated with reductions of oxidative stress in the vasculature and kidney and associated decreases in albuminuria. Effects of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibition on oxidative stress in the kidney and filtration barrier integrity are poorly understood. To investigate, we used transgenic TG(mRen2)27 (Ren2) rats, which harbor the mouse renin transgene and renin-angiotensin system activation, and an immortalized murine podocyte cell line. We treated young, male Ren2 and Sprague-Dawley rats with rosuvastatin (20 mg/kg IP) or placebo for 21 days. Compared with controls, we observed increases in systolic blood pressure, albuminuria, renal NADPH oxidase activity, and 3-nitrotryosine staining, with reductions in the rosuvastatin-treated Ren2. Structural changes on light and transmission electron microscopy, consistent with periarteriolar fibrosis and podocyte foot-process effacement, were attenuated with statin treatment. Nephrin expression was diminished in the Ren2 kidney and trended to normalize with statin treatment. Angiotensin II–dependent increases in podocyte NADPH oxidase activity and subunit expression (NOX2, NOX4, Rac, and p22phox) and reactive oxygen species generation were decreased after in vitro statin treatment. These data support a role for increased NADPH oxidase activity and subunit expression with resultant reactive oxygen species formation in the kidney and podocyte. Furthermore, statin attenuation of NADPH oxidase activation and reactive oxygen species formation in the kidney/podocyte seems to play roles in the abrogation of oxidative stress-induced filtration barrier injury and consequent albuminuria.
PMCID: PMC2683987  PMID: 18172055
angiotensin II; albuminuria; glomerular filtration barrier; transgenic Ren2 rat; rosuvastatin
16.  A reliable and efficient method for deleting operational sequences in PACs and BACs 
Nucleic Acids Research  2002;30(10):e41.
P1-derived artificial chromosomes (PACs) and bacterial artificial chromosomes (BACs) have become very useful as tools to study gene expression and regulation in cells and in transgenic mice. They carry large fragments of genomic DNA (≥100 kb) and therefore may contain all of the cis-regulatory elements required for expression of a gene. Because of this, even when inserted randomly in the genome, they can emulate the native environment of a gene resulting in a tightly regulated pattern of expression. Because these large genomic clones often contain DNA sequences which can manipulate chromatin at the local level, they become immune to position effects which affect expression of smaller transgenes, and thus their expression is proportional to copy number. Transgenic mice containing large BACs and PACs have become excellent models to examine the regulation of gene expression. Their usefulness would certainly be increased if easy and efficient methods are developed to manipulate them. We describe herein a method to make deletion mutations reliably and efficiently using a novel modification of the Chi-stimulated homologous recombination method. Specifically, we generated and employed a Lox511 ‘floxed’ CAM resistance marker that first affords selection for homologous recombination in Escherichia coli, and then can be easily deleted leaving only a single Lox511 site as the footprint.
PMCID: PMC115295  PMID: 12000846

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