MYOFIBROBLASTS AND THE PROGRESSION OF DIABETIC NEPHROPATHY

Background. The cellular mediators of progressive renal fibrosis in di abetic nephropathy remain unknown. Myofibroblasts have been implicated in the pathogenesis of experimental and clinical renal fibrosis. Thei r role in the progression of diabetic nephropathy is the subject of th is study. Subjects and methods. We have studied by immunohistochemistr y the expression of cytoskeletal proteins associated with the activati on of myofibroblasts; alpha-smooth-muscle actin (alpha-SMA), vimentin (Vi) and desmin (D), in the kidneys of 25 patients with diabetic nephr opathy (5 patients had a superimposed glomerulonephritis). Comparisons were made with normal tissue from three kidneys removed for renal-cel l carcinoma. Correlations were studied between clinical and biochemica l parameters with the expression of renal cytoskeletal proteins. Resul ts. In normal kidneys, cells expressing alpha-SMA were confined to the vascular media and adventitia while immunoreactive Vi was detected in glomerular epithelial cells. In diabetic kidneys, cells expressing al pha-SMA were detected primarily in the renal interstitium and to a les ser extent in some glomeruli in association with mesangial proliferati on. Vimentin immunostain decreased in glomeruli displaying diabetic hy alinosis and sclerosis. By contrast, strong Vi immunoreactivity was no ted in atrophic diabetic tubules and to a lesser extent in the interst itium. Desmin was not detected in either normal or diabetic kidneys. C lose correlations were observed between the expression of renal cytosk eletal proteins and the progression of renal insufficiency. Interstiti al a-SMA proved to be a predictor of progressive diabetic nephropathy (R(2) for 1/serum Cr slope=0.608, P=0.00001). This predictive value wa s superior to, and independent from, that of the best conventional his tological predictive parameters; tubular atrophy (R(2)=0.477, P=0.0000 4) and interstitial fibrosis (R(2)=0.28, P=0.001). Conclusion. We have demonstrated in this study the neoexpression of cytoskeletal proteins within diabetic kidneys. This has allowed the identification of new p redicting histological markers for the progression of diabetic nephrop athy.