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Posttranslational regulation of NO synthase activity in the renal medulla of diabetic rats

¹Vascular Biology Center, Departments of ²Pharmacology and Toxicology and ³Surgery, Medical College of Georgia, Augusta, Georgia; and ⁴Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, Nebraska

Submitted 8 April 2004 ; accepted in final form 17 September 2004

Shear stress increases nitric oxide (NO) production by endothelial cells, inner medullary collecting duct cells, and thick ascending limb. We postulated that the osmotic diuresis accompanying type 1 diabetes is associated with increased NO synthase (NOS) activity and/or expression in the renal medulla. Diabetes was induced by injection of streptozotocin, with insulin provided to maintain moderate hyperglycemia (Hyp) or euglycemia (Eug) for 3 wk. Sham rats received vehicle treatments. A separate group of rats (Phz) received phlorizin to produce a glucose-dependent osmotic diuresis. Renal medullary NOS1 and NOS2 activities did not differ between groups, whereas NOS3 activity was significantly increased in Hyp. Neither NOS1 nor NOS3 protein levels differed significantly between groups. Reduced phosphorylation of NOS3 at Thr⁴⁹⁵ and Ser⁶³³ was evident in medullary homogenates from Hyp rats, with no difference apparent at Ser¹¹⁷⁷. Immunohistochemical analysis indicated prominent expression of pThr⁴⁹⁵NOS3 in the thick ascending limb and collecting duct of Sham and Phz rats. Hyp rats displayed staining in the collecting duct but minimal thick ascending limb staining. Immunostaining with anti-pSer¹¹⁷⁷NOS3 was evident only in the thick ascending limb, with no apparent differences between groups. In summary, glucose-dependent osmotic diuresis alone did not alter NOS activity or expression in the renal medulla. Diabetic hyperglycemia increased medullary NOS3 activity without a concomitant increase in NOS3 protein levels; however, NOS3 phosphorylation was reduced at Thr⁴⁹⁵ and Ser⁶³³. Thus changes in the phosphorylation of NOS at known regulatory sites might represent the primary mechanism underlying increased renal medullary NOS activity in diabetic hyperglycemia.

streptozotocin; phosphorylation; phlorizin; nitric oxide synthase; NOS3; NOS1

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