Study on Mechanisms for Progression and Regression of Diabetic Glomerular Injury and Role of Novel Humoral Factors

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In order to explore the mechanisms for progression and regression of diabetic glomerular injury and to investigate the roles of novel humoral factors in such processes, we examined the in vivo effects of the CCN family (CCN1, CCN2) that are extracellular matrix-associated secretory proteins, fat tissue-derived hormone leptin, and cardiac hormone natriuretic peptides, using genetically engineered mouse models.CCN1 (connective tissue growth factor, CTGF), a profibrotic protein mediating fibrogenic properties of TGF-β, is expressed normally in glomerular podocytes and upregulated in diabetic nephropathy. We established the podocyte-specific CTGF-transgenic (Tg) mice using human nephrin promoter, and examined effects of CTGF overexpression in the diabetic milieu. CTGF-Tg mice did not show any abnormality at basal state, but exhibited significantly enhanced proteinuria (〜3-fold) compared with wild-type mice during the course of streptozotocin (STZ)-induced diabetic nephropathy. CTGF-Tg mice … More also showed more pronounced mesangial expansion, with decreased number and vacuolar changes of podocytes, indicating aggravation of podocyte injury. In contrast, CCN2 (cysteine-rich protein 61, Cyr61), another podocyte-derived humoral factor, is suggested to have renoprotective properties. In podocyte-specific Cyr61-Tg mice with the nephrin promoter, glomerular hypertrophy was less prominent during STZ-induced diabetes as compared with wild-type mice.We then investigated renal abnormalities in A-ZIP/F-1 mice, a lipoatrophic diabetes model. This mouse model revealed markedly progressive nephrotic-range proteinuria, remarkable glomerular hypertrophy with mesangial expansion, and glomerular basement membrane thickening, which are characteristics of human diabetic nephropathy at advanced stages. Transgenic overexpression of the leptin gene or pharmacological administration of leptin into this model almost completely normalized such abnormal phenotypes. Finally, chronic overproduction of brain natriuretic peptide (BNP) in BNP-Tg mice was significantly resistant against diabetic glomerular injury in terms of proteinuria, mesangial expansion, and mesangial upregulation of the ERK/TGF-β cascade. These findings suggest the therapeutic potential of leptin and natriuretic peptides in diabetic nephropathy. Less