Cardinal Role of the Intrarenal Renin-Angiotensin System in the Pathogenesis of Diabetic Nephropathy

Kobori, Hiroyuki; Kamiyama, Masumi; Harrison‐Bernard, Lisa M.; Navar, L. Gabriel

doi:10.2310/jim.0b013e31827c28bb

Cited by 54 publications

(49 citation statements)

References 104 publications

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“…In addition to renal ACE, HF diet elevated Ang II in RIF of wild-type mice together with blood pressure and UACR, as was observed previously (5). The importance of RAS in the regulation of blood pressure and development of albuminuria is well recognized (20,26,(41)(42). Ang II is the principal RAS peptide regulating blood pressure and contributing to increased urinary albumin.…”

Section: Discussionsupporting

confidence: 60%

High-fat diet amplifies renal renin angiotensin system expression, blood pressure elevation, and renal dysfunction caused by Ceacam1 null deletion

Culver

Quadri

et al. 2015

American Journal of Physiology-Endocrinology and Metabolism

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Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAMl), a substrate of the insulin receptor tyrosine kinase, regulates insulin action by promoting insulin clearance. Global null mutation of Ceacam1 gene (Cc1(-/-)) results in features of the metabolic syndrome, including insulin resistance, hyperinsulinemia, visceral adiposity, elevated blood pressure, and albuminuria. It also causes activation of the renal renin-angiotensin system (RAS). In the current study, we tested the hypothesis that high-fat diet enhances the expression of RAS components. Three-month-old wild-type (Cc1(+/+)) and Cc1(-/-) mice were fed either a regular or a high-fat diet for 8 wk. At baseline under regular feeding conditions, Cc1(-/-) mice exhibited higher blood pressure, urine albumin-to-creatinine ratio (UACR), and renal expression of angiotensinogen, renin/prorenin, angiotensin-converting enzyme, (pro)renin receptor, angiotensin subtype AT1 receptor, angiotensin II, and elevated PI3K phosphorylation, as detected by p85α (Tyr(508)) immunostaining, inflammatory response, and the expression of collagen I and collagen III. In Cc1(+/+) mice, high-fat diet increased blood pressure, UACR, the expression of angiotensin-converting enzyme and angiotensin II, PI3K phosphorylation, inflammatory response, and the expression of collagen I and collagen III. In Cc1(-/-) mice, high-fat intake further amplified these parameters. Immunohistochemical staining showed increased p-PI3K p85α (Tyr(508)) expression in renal glomeruli, proximal, distal, and collecting tubules of Cc1(-/-) mice fed a high-fat diet. Together, this demonstrates that high-fat diet amplifies the permissive effect of Ceacam1 deletion on renal expression of all RAS components, PI3K phosphorylation, inflammation, and fibrosis.

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Section: Discussionsupporting

confidence: 60%

High-fat diet amplifies renal renin angiotensin system expression, blood pressure elevation, and renal dysfunction caused by Ceacam1 null deletion

Culver

Quadri

et al. 2015

American Journal of Physiology-Endocrinology and Metabolism

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“…44,45 These findings are relevant because activation of the renin-angiotensin system in the diabetic kidney has been shown to promote renal injury. 46,47 Angiotensin II induces upregulation of Nox1. 48 Therefore, it has been postulated that Nox1 could play an important role in the development and progression of diabetic nephropathy.…”

Section: Discussionmentioning

confidence: 99%

Genetic Targeting or Pharmacologic Inhibition of NADPH Oxidase Nox4 Provides Renoprotection in Long-Term Diabetic Nephropathy

Jha

Gray

Barit

et al. 2014

Journal of the American Society of Nephrology

317

333

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Diabetic nephropathy may occur, in part, as a result of intrarenal oxidative stress. NADPH oxidases comprise the only known dedicated reactive oxygen species (ROS)-forming enzyme family. In the rodent kidney, three isoforms of the catalytic subunit of NADPH oxidase are expressed (Nox1, Nox2, and Nox4). Here we show that Nox4 is the main source of renal ROS in a mouse model of diabetic nephropathy induced by streptozotocin administration in ApoE 2/2 mice. Deletion of Nox4, but not of Nox1, resulted in renal protection from glomerular injury as evidenced by attenuated albuminuria, preserved structure, reduced glomerular accumulation of extracellular matrix proteins, attenuated glomerular macrophage infiltration, and reduced renal expression of monocyte chemoattractant protein-1 and NF-kB in streptozotocin-induced diabetic ApoE 2/2 mice. Importantly, administration of the most specific Nox1/4 inhibitor, GKT137831, replicated these renoprotective effects of Nox4 deletion. In human podocytes, silencing of the Nox4 gene resulted in reduced production of ROS and downregulation of proinflammatory and profibrotic markers that are implicated in diabetic nephropathy. Collectively, these results identify Nox4 as a key source of ROS responsible for kidney injury in diabetes and provide proof of principle for an innovative small molecule approach to treat and/or prevent chronic kidney failure.

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“…Because podocyte injury also develops under normoglycemic conditions, factors other than glucose may also activate podocyte CB 1 R. A likely candidate is the RAS, the other major driver of diabetic nephropathy (37,38), activation of which in ZDF rats is indicated by the elevated plasma angiotensin II and aldosterone levels and the increased renal expression of Agtr1 (Fig. 4A).…”

Section: Discussionmentioning

confidence: 99%

Overactive cannabinoid 1 receptor in podocytes drives type 2 diabetic nephropathy

Jourdan¹,

Szanda²,

Rosenberg

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

111

145

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Diabetic nephropathy is a major cause of end-stage kidney disease, and overactivity of the endocannabinoid/cannabinoid 1 receptor (CB 1 R) system contributes to diabetes and its complications. Zucker diabetic fatty (ZDF) rats develop type 2 diabetic nephropathy with albuminuria, reduced glomerular filtration, activation of the reninangiotensin system (RAS), oxidative/nitrative stress, podocyte loss, and increased CB 1 R expression in glomeruli. Peripheral CB 1 R blockade initiated in the prediabetic stage prevented these changes or reversed them when animals with fully developed diabetic nephropathy were treated. Treatment of diabetic ZDF rats with losartan, an angiotensin II receptor-1 (Agtr1) antagonist, attenuated the development of nephropathy and down-regulated renal cortical CB 1 R expression, without affecting the marked hyperglycemia. In cultured human podocytes, CB 1 R and desmin gene expression were increased and podocin and nephrin content were decreased by either the CB 1 R agonist arachydonoyl-2′-chloroethylamide, angiotensin II, or high glucose, and the effects of all three were antagonized by CB 1 R blockade or siRNA-mediated knockdown of CNR1 (the cannabinoid type 1 receptor gene). We conclude that increased CB 1 R signaling in podocytes contributes to the development of diabetic nephropathy and represents a common pathway through which both hyperglycemia and increased RAS activity exert their deleterious effects, highlighting the therapeutic potential of peripheral CB 1 R blockade.iabetic nephropathy, a highly prevalent and serious complication of both type 1 and type 2 diabetes mellitus and a leading cause of renal failure, is characterized by albuminuria, decreased glomerular filtration rate (GFR), mesangial expansion, thickening of the glomerular basement membrane, and glomerular sclerosis (1). Multiple mechanisms have been implicated in the development of diabetic nephropathy, including activation of the renin-angiotensin system (RAS) (2), increase in oxidative (3) and nitrosative/nitrative stress (4), as well as an increase in local inflammation (5).The endocannabinoid system plays a well-documented role in obesity and its metabolic complications, including insulin resistance and type 2 diabetes (T2DM). Globally acting cannabinoid 1 receptor (CB 1 R) antagonists/inverse agonists improve obesity-related insulin resistance, dyslipidemia, fatty liver, and β-cell loss, and attenuate obesity-related inflammatory changes both in preclinical models of diet-induced or genetic obesity and in clinical trials in overweight subjects with metabolic syndrome (reviewed in refs. 6 and 7). Global CB 1 R blockade also has beneficial effects in mouse models of type 1 and type 2 diabetic nephropathy (8-11). However, the therapeutic development of this class of compounds has been halted because of adverse neuropsychiatric side effects in a small proportion of treated subjects (12). Recent studies in rodent models have demonstrated that peripherally restricted CB 1 R antagonists are as effective as globally acti...

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Cardinal Role of the Intrarenal Renin-Angiotensin System in the Pathogenesis of Diabetic Nephropathy

Cited by 54 publications

References 104 publications

High-fat diet amplifies renal renin angiotensin system expression, blood pressure elevation, and renal dysfunction caused by Ceacam1 null deletion

High-fat diet amplifies renal renin angiotensin system expression, blood pressure elevation, and renal dysfunction caused by Ceacam1 null deletion

Genetic Targeting or Pharmacologic Inhibition of NADPH Oxidase Nox4 Provides Renoprotection in Long-Term Diabetic Nephropathy

Overactive cannabinoid 1 receptor in podocytes drives type 2 diabetic nephropathy

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