Role of coagulation factor 3 in diabetic nephropathy

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Diabetic nephropathy (DN)is the leading cause of end stage renal disease, and the number of patients with DN has been increasing rapidly. 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. Here we have demonstrated that eNOS-/-mice with diabetes develop severe nephropathy. 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, initiator of coagulation, likely plays a significant role in the DN of the eNOS-/-diabetic mice. Strategies to ameliorate hypercoagulability could be useful for treatment of DN.