Abnormal renal hemodynamic response to reduced renal perfusion pressure in diabetic rats: role of NO

Tolins, Jonathan P.; Shultz, Pamela J.; Raij, Leopoldo; Brown, Daniel F.; Mauer, S. Michael

doi:10.1152/ajprenal.1993.265.6.f886

Cited by 70 publications

(88 citation statements)

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“…However, considering the fact that eNOS and CAV-1 form an inhibitory complex, reduced CAV-1 expression may be interpreted as a factor favoring NOS enzymatic activity. This observation would be consistent with data suggesting enhanced NO dependency of renal hemodynamics in hyperfiltering diabetic rats and the role of NO in the pathogenesis of hyperfiltration (7)(8)(9) and with those reports suggesting a role for eNOS-derived NO in this process (26,32,33). However, the latter reports relied on measurements of eNOS expression and constitutive renal NOS activity, and the role of eNOS could not be verified by measurement of renal hemodynamic responses to specific eNOS inhibitors.…”

Section: Enos and Cav-1 In The Diabetic Kidneysupporting

confidence: 89%

“…For instance, in vitro studies suggest defective endothelium-dependent (i.e., endothelial NO synthase [eNOS]-dependent) NO production or function in the diabetic kidney (3)(4)(5)(6). These studies contrast with observations from in vivo studies with NO synthase (NOS) inhibitors, which show substantial NO dependency of renal hemodynamics in hyperfiltering diabetic rats (7)(8)(9).…”

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confidence: 69%

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Altered Endothelial Nitric Oxide Synthase Targeting and Conformation and Caveolin-1 Expression in the Diabetic Kidney

et al. 2006

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Experimental diabetes is associated with complex changes in renal nitric oxide (NO) bioavailability. We explored the effect of diabetes on renal cortical protein expression of endothelial NO synthase (eNOS) with respect to several determinants of its enzymatic function, such as eNOS expression, membrane localization, phosphorylation, and dimerization, in moderately hyperglycemic streptozotocininduced diabetic rats compared with nondiabetic control rats and diabetic rats with intensive insulin treatment to achieve near-normal metabolic control. We studied renal cortical expression and localization of caveolin-1 (CAV-1), an endogenous modulator of eNOS function. Despite similar whole-cell eNOS expression in all groups, eNOS monomer and dimer in membrane fractions were reduced in moderately hyperglycemic diabetic rats compared with control rats; the opposite trend was apparent in the cytosol. Stimulatory phosphorylation of eNOS (Ser1177) was also reduced in moderately hyperglycemic diabetic rats. eNOS colocalized and interacted with CAV-1 in endothelial cells throughout the renal vascular tree both in control and moderately hyperglycemic diabetic rats. However, the abundance of membrane-localized CAV-1 was decreased in diabetic kidneys. Intensive insulin treatment reversed the effects of diabetes on each of these parameters. In summary, we observed diabetes-mediated alterations in eNOS and CAV-1 expression that are consistent with the view of decreased bioavailability of renal eNOS-derived NO.

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Section: Enos and Cav-1 In The Diabetic Kidneysupporting

confidence: 89%

contrasting

confidence: 69%

Altered Endothelial Nitric Oxide Synthase Targeting and Conformation and Caveolin-1 Expression in the Diabetic Kidney

et al. 2006

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“…Therefore, it could be hypothesised that the renal vascular bed responds in a paradoxical fashion during diabetes, with an enhanced endothelium-dependent relaxation to acetylcholine. This enhanced relaxation could contribute to the renal hyperperfusion and hyperfiltration Ž observed in diabetes Tolins et al, 1993;Sugimoto et al, . 1998 .…”

Section: Discussionmentioning

confidence: 99%

“…markedly abnormal in diabetic rats Mauer et al, 1990 , which suggests that vasodilator factors may be abnormally Ž . active in diabetes Tolins et al, 1993 . In the kidney, NO plays an important role in the regulation of renal hemodynamics not only in physio-Ž . logical conditions Kone and Baylis, 1997 , but also in Ž .…”

Section: Introductionmentioning

confidence: 99%

Diabetes potentiates acetylcholine-induced relaxation in rabbit renal arteries

Alabadí

Miranda

Lloréns

et al. 2001

European Journal of Pharmacology

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The response of rabbit renal arteries to acetylcholine and its endothelial modulation in diabetes were investigated. Acetylcholine induced concentration-related endothelium-dependent relaxation of renal arteries that was significantly more potent in diabetic rabbits G Ž . than in control rabbits. Pretreatment with N -nitro-L-arginine L-NOArg , indomethacin, or L-NOArg plus indomethacin induced partial inhibition of acetylcholine-induced relaxation. Inhibition induced by L-NOArg plus indomethacin was significantly higher in arteries from diabetic rabbits than in arteries from control rabbits. In renal arteries depolarised with KCl 30 mM and incubated with L-NOArg plus indomethacin, acetylcholine-induced relaxation was almost abolished in both groups of rabbits and this response was not different from that obtained in arteries without endothelium. Sodium nitroprusside induced concentration-dependent relaxation of renal arteries from control and diabetic rabbits without significant differences between the two groups of animals. These results suggest that diabetes potentiates the acetylcholine-induced relaxation in rabbit renal arteries. Increased release of nitric oxide and prostacyclin could be responsible for the enhanced relaxant potency of acetylcholine in diabetes. q

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“…7 Reduced bioavailability of NO under high-glucose conditions, as demonstrated in in vitro studies, contradicts in vivo studies where an enhanced renal NO production and/or its activity have been shown under hyperglycemic conditions. [7][8][9] This raises the question whether or not hyperglycemia is directly responsible for these complications or they appear as secondary effect due to impaired NO regulation. Differential mechanisms have been postulated with the use of in vitro cultures of vascular endothelial cells.…”

mentioning

confidence: 99%

Diabetic eNOS knockout mice develop distinct macro- and microvascular complications

Mohan

Reddick

Musi

et al. 2008

Laboratory Investigation

107

119

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Functional consequences of impaired endothelial nitric oxide synthase (eNOS) activity causing organ-specific abnormalities on a diabetic setting are not completely understood. In this study, we extensively characterized a diabetic mouse model (lepr db/db ) in which eNOS expression is genetically disrupted (eNOS À/À ). The eNOS À/À / lepr db/db double-knockout (DKO) mice developed obesity, hyperglycemia, hyperinsulinemia and hypertension. Analysis of tissues from DKO mice showed large islets in the pancreas and fat droplets in hepatocytes. Interestingly, the aorta was normal and atherogenic lesions were not observed. Abnormalities in the aorta including poor re-endothelialization and increased medial wall thickness were evident only in response to deliberate injury. In contrast, significant glomerular capillary damage in the kidney was identified, with DKO mice demonstrating a robust diabetic nephropathy similar to human disease. The vascular and renal impairments in DKO mice were pronounced despite lower fasting plasma glucose levels compared to lepr db/db mice, indicating that eNOS is a critical determinant of hyperglycemia-induced organ-specific complications and their severity in diabetes. Results provide the first evidence that absence of eNOS in diabetes has a greater deleterious effect on the renal microvasculature than on the larger aortic vessel. The DKO model may suggest novel therapeutic strategies to prevent both vascular and renal complications of diabetes. KEYWORDS: diabetes; endothelial dysfunction; eNOS; micro-and macrovasculature; nephropathy and vasculopathy Macro-and microangiopathy including accelerated atherosclerosis and nephropathy are the most common complications of diabetes. Reduced bioavailabilty of nitric oxide (NO), due to impaired nitric oxide synthase (NOS) activity, is implicated in the generation of these abnormalities. 1-3 NO is formed from L-Arginine by three isoforms of NOS with stoichiometric production of L-citrulline. Among the three isoforms, endothelial NOS (eNOS) is constitutively expressed predominantly in the macrovascular endothelium and along the renal microvascular tree. Basal release of eNOS-driven NO by endothelial cells contributes to the maintenance of normal vasodilatory tone and thromboresistance. Under conditions of hyperglycemia and associated increase in advanced glycation end products, there is excessive generation of superoxide, which interacts with NO resulting in the formation of peroxynitrites. The peroxynitrites oxidize tetrahydrobiopterin, an important cofactor involved in normal eNOS activity. The deficiency of tetrahydrobiopterin causes eNOS uncoupling, which results in increased generation of superoxide rather than NO. Overall, superoxide generation is amplified in macrovessels in diabetes with concomitant reduction in the level of bioavailable NO.Nitric oxide also acts as a potent modulator of renal function and controls both afferent and efferent vascular tone, glomerular ultrafiltration coefficient 4,5 and medullary blood flow. 6 However, the pr...

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Abnormal renal hemodynamic response to reduced renal perfusion pressure in diabetic rats: role of NO

Cited by 70 publications

References 0 publications

Altered Endothelial Nitric Oxide Synthase Targeting and Conformation and Caveolin-1 Expression in the Diabetic Kidney

Altered Endothelial Nitric Oxide Synthase Targeting and Conformation and Caveolin-1 Expression in the Diabetic Kidney

Diabetes potentiates acetylcholine-induced relaxation in rabbit renal arteries

Diabetic eNOS knockout mice develop distinct macro- and microvascular complications

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