Authors: Toblli, Jorge Eduardo; Cao, Gabriel Fernando; Giani, Jorge Fernando; Angerosa, Margarita; Dominici, Fernando Pablo; Gonzalez Cadavid, Nestor F.
Publication Date: 2011.
Language: English.
Abstract:
BACKGROUND/AIMS: Pioglitazone and other thiazolidinediones are renoprotective in diabetic nephropathy at doses that normalize glycemia, presumably as a consequence of glycemic control. However, low doses of pioglitazone that did not normalize glycemia in rat models of type 2 diabetes prevented tubulointerstitial fibrosis and glomerulosclerosis through counteracting inflammation, oxidative stress, cell cycle arrest, and fibrosis. The current work tested whether this low-dose treatment also reduces other fibrosis and inflammation factors in the diabetic kidney and prevents tubular cell loss, endothelial damage, and abnormal angiogenesis. METHODS: ZDF fa/fa rats (ZDF) were fed for 4 months chow with 0.001% pioglitazone, and the untreated ZDF and the non-diabetic lean Zucker rats (LZR) received regular chow. Proteinuria, creatinine clearance, blood pressure, and renal quantitative histopathology markers were determined. RESULTS: Correction of renal function in ZDF by pioglitazone, occurring with a glycemia >250 mg/dl, was accompanied by normalization of the renal levels of connective tissue growth factor and fibronectin (fibrosis), TNF-α, interleukin-6 and MCP-1 (inflammation), megalin (tubular cells), the PCNA/caspase-3 ratio (positive cell turnover), VEGF (abnormal angiogenesis), and the ratio between eNOS and iNOS (endothelial dysfunction). CONCLUSION: This supports mechanisms for the renoprotective effects of pioglitazone in diabetes additional to glycemic control.
Author affiliation: Toblli, Jorge Eduardo. Hospital Alemán. Laboratorio de Medicina Experimental; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Author affiliation: Cao, Gabriel Fernando. Hospital Alemán. Laboratorio de Medicina Experimental; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Author affiliation: Giani, Jorge Fernando. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Físico-Química Biológicas "Prof. Alejandro C. Paladini". Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Química y Físico-Química Biológicas; Argentina
Author affiliation: Angerosa, Margarita. Hospital Alemán. Laboratorio de Medicina Experimental; Argentina
Author affiliation: Dominici, Fernando Pablo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Físico-Química Biológicas "Prof. Alejandro C. Paladini". Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Química y Físico-Química Biológicas; Argentina
Author affiliation: Gonzalez Cadavid, Nestor F.. University of California at Los Angeles; Estados Unidos. Charles Drew University; Estados Unidos
Repository: CONICET Digital (CONICET). Consejo Nacional de Investigaciones Científicas y Técnicas