Investigation of pathogenesis of albuminuria in chronic kidney disease and its association with cardiovascular complications

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Albuminuria is an independent risk marker for development of cardiovascular disease. We hypothesized that albuminuria could be caused by glomerular endothelial injuries/dysfunctions. We have successfully developed the novel in vivo-imaging technique by which we can visualize microcirculation and filtration status by using 2-phton lasermicroscopy. We found that in diabetes, endothelial nitric oxide synthase (eNOS) produces superoxide anion rather than nitric oxide, referred to as "eNOS uncoupling," which contributes to endothelial dysfunction, albuminuria, and diabetic nephropathy. Reduced levels of endothelium-derived tetrahydrobiopterin (BH4), an essential cofactor for eNOS, promote eNOS uncoupling. We also demonstrated that renin-angiotensin system is deeply associated with generation of oxidative stress through activation of NADPH-oxidase. We have elucidated that maintenance of endothelial integrity ameliorates diabetic nephropathy.