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

¹ Division of Nephrology and Hypertension, Oregon Health and Science University, Portland, Oregon
² Department of Medicine, Oregon Health and Science University, Portland, Oregon
³ Diabetes Center, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
⁴ Research Service, Portland VA Medical Center, Portland, Oregon
⁵ Department of Behavioral Neuroscience, Oregon Health and Science University, Portland, Oregon

Address correspondence and reprint requests to Radko Komers, MD, PhD, Division of NephrologyHypertension PP262, Oregon HealthScience University, 3314 SW US Veterans Hospital Rd., Portland, OR 97239. E-mail: komersr{at}ohsu.edu

Abbreviations: CAV-1, caveolin-1; eNOS, endothelial nitric oxide synthase; NOS, nitric oxide synthase

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 streptozotocin-induced 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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