Journal of Nephrology & Therapeutics

eNOS and Diabetic Nephropathy

Abstract

Feng Li ,Nobuyuki Takahashi *

Diabetic nephropathy (DN) is the leading cause of end stage renal disease (ESRD) and the number of patients with DN has been increasing rapidly. Development of new effective therapeutic strategies of DN is slow at least partly because of a lack of animal models that recapitulate the features of human DN. Human variants of the endothelial nitric oxide synthase gene (eNOS, NOS3 ) that produce reduced amounts of nitric oxide (NO) are positively associated with DN, although proof of causation is lacking. Recently, several investigators have established animal models of advanced DN using mice unable to synthesize eNOS and have demonstrated that eNOS -/- mice with diabetes develop severe nephropathy. It has been also shown that a high fat diet worsens the DN of the diabetic mice lacking eNOS. However, complete absence of eNOS has not been reported in humans, although reduced levels are not infrequent. Accordingly, heterozygous eNOS +/- mice have been made diabetic and they demonstrated that the decrease in eNOS/ NO comparable to that of NOS3 polymorphisms is sufficient to cause exacerbation of DN. Increased expression of tissue factor (TF), initiator of coagulation, plays a significant role in the DN of the eNOS -/- diabetic mice, as well as in diabetic mice having wild type eNOS. Strategies to ameliorate hypercoagulability could be useful for treatment of DN.