Role of proximal tubule injury in the pathogenesis of diabetic nephropathy

Diabetic nephropathy (DN) has been traditionally considered as a primary glomerular disease. We suggest that the kidney tubule plays a primary role in the development of DN, and that subsequent tubulointerstitial injury may lead to glomerular changes in diabetes. We will investigate if selective proximal tubule injury alone can accelerate diabetic kidney disease in a genetic model of type 1 diabetes (Akita mice). For these studies, we have crossed a mouse containing the tubule-specific Six2-Cre allele with a mouse transgenic for a Cre-inducible simian diphtheria toxin receptor (iDTR). Six2-Cre/iDTR mice will be bred with Akita mice to create diabetic animals which develop isolated proximal tubule damage upon administration of diphtheria toxin. The severity of the kidney disease will then be quantitated by determining the effects of targeted tubular damage on the severity of albuminuria, urinary kidney injury molecule (KIM)-1 excretion, hypertension, kidney function, renal hypertrophy, and renal histopathological abnormalities in the tubulointerstitium (interstitial fibrosis and tubular atrophy, and vascular rarefaction) and glomeruli (mesangial expansion, matrix accumulation, and basement membrane thickening) by both light microscopy and electron microscopy, as well as expression of pro-fibrotic growth factors at both the mRNA and protein levels. If the proposed studies are successful, the findings will provide the conceptual framework for the development of novel pharmacological therapies that protect the proximal tubule against injury for the treatment of diabetic kidney disease in humans.