Renoprotective mechanisms of telmisartan on renal injury and inflammation in SHRSP.Z-Lepr fa /IzmDmcr rats
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ORIGINAL ARTICLE
Renoprotective mechanisms of telmisartan on renal injury and inflammation in SHRSP.Z-Leprfa/IzmDmcr rats Fumihiro Sugiyama • Naohiko Kobayashi • Mayuko Ishikawa • Sho Onoda • Toshihiko Ishimitsu
Received: 11 September 2012 / Accepted: 11 December 2012 Ó Japanese Society of Nephrology 2012
Abstract Background SHRSP.Z-Leprfa/IzmDmcr (SHRSP fatty) rats create a new animal model of metabolic syndrome. However, the renoprotective effect of telmisartan therapy and its underlying mechanisms in SHRSP fatty rats remain unknown. We evaluate the effects of long-term telmisartan therapy on renal dysfunction, podocyte injury, inflammation, and transforming growth factor-b1 (TGF-b1)/Smad, epithelial-mesenchymal transition (EMT), mitogen-activated protein kinase (MAPK), Rho-kinase, and cell-cycle progression pathway in the renal cortex of SHRSP fatty rats. Methods Seven-week-old male SHRSP fatty rats were treated with vehicle, telmisartan, and hydralazine for 8 weeks. Age-matched male Wistar-Kyoto/Izumo rats served as a control group. Results Vehicle-treated SHRSP fatty rats developed proteinuria and renal dysfunction, which in the telmisartan group was less than the vehicle and hydralazine group without changing blood pressure. Glomerulosclerosis and interstitial fibrosis were impaired in SHRSP fatty rats, and the renal damage in the telmisartan group was less than the vehicle and hydralazine groups. Decreased expression of nephrin and podocin and increased desmin-positive area in SHRSP fatty rats were restored by telmisartan but not hydralazine. TGF-b1/Smad, EMT marker, MAPK, Rhokinase, and cell-cycle progression pathways were upregulated in SHRSP fatty rats, and these increased proteins in the telmisartan group were less than the vehicle and
F. Sugiyama N. Kobayashi (&) M. Ishikawa S. Onoda T. Ishimitsu Department of Cardiology and Nephrology, Dokkyo Medical University School of Medicine, Mibu, Tochigi 321-0293, Japan e-mail: [email protected]
hydralazine group. Telmisartan administration resulted in significant suppression in tumor necrosis factor-a expression and nuclear factor-jB phosphorylation. Conclusion Long-term telmisartan therapy may improve renal dysfunction, glomerulosclerosis, podocyte injury, and inflammation associated with EMT, TGF-b/Smad, MAPK, Rho-kinase pathway in SHRSP fatty rats. Thus, telmisartan may have significant therapeutic potential for metabolic syndrome. Keywords Telmisartan Metabolic syndrome Nephrosclerosis
Introduction SHRSP.Z-Leprfa/IzmDmcr (SHRSP fatty) rats were established by crossing stroke-prone spontaneously hypertensive rats (SHRSP/Izm) with Zucker fatty (fa/fa) rats to create a new animal model of metabolic syndrome [1]. SHRSP fatty rats carry the leptin receptor OB-Rb gene mutation found in fa/fa rats and become obese while developing hypertension. These rats develop spontaneous severe hypertension and obesity and exhibit metabolic abnormalities similar to those found in human metabolic syndrome. SHRSP fatty rats have been used in studies to e
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