BACKGROUND: Recent studies revealed that sirtuin 1 (SIRT1) has a relation to the mechanism of transforming growth factor-beta (TGF-beta) mediated apoptosis in glomerular mesangial cells and plays an important role in blood pressure regulation. It has been suggested that SIRT1 contributes to the renoprotective effect of angiotensin receptor blocker (ARB), but this has not yet become clearly recognized. In this study, we examined the relationship between SIRT1 and the therapeutic effect of olmesartan on renal injury in nephrectomized spontaneously hypertensive rats (SHRs). METHODS: Male Wistar rats and 5/6 nephrectomized (5/6Nx) SHRs were assigned to 5 groups as follows: group A, Wistar rats; group B, Wistar rats administered high-dose olmesartan (15 mg/kg/day); group C, 5/6Nx SHRs; group D, 5/6Nx SHRs administered low-dose (3 mg/kg/day) olmesartan; and group E, 5/6Nx SHRs administered high-dose olmesartan. The drugs were administered for 12 weeks. Blood pressure and urinary protein excretion were measured every 4 weeks. Serum creatinine, glomerular sclerosis, SIRT1 mRNA level, TGF-beta mRNA level and klotho mRNA level were measured at the end of the examination. RESULTS: Systolic blood pressure, urinary protein excretion, serum creatinine and glomerular sclerosis in Wistar rats were significantly lower than that of 5/6Nx SHRs. Among 5/6Nx SHRs, high doses of olmesartan significantly decreased urinary protein excretion, serum creatinine and glomerular sclerosis compared to the non-treated and low-dose olmesartan groups. Expression of SIRT1 and klotho mRNA were significantly downregulated in 5/6Nx SHRs; however, olmesartan did not attribute to any change in gene expression. Expression of TGF-beta mRNA was significantly increased in 5/6Nx SHRs, and olmesartan did not affect the level of TGF-beta mRNA expression. CONCLUSION: Expression of SIRT1 is decreased in 5/6Nx SHRs compared to Wistar rats. Olmesartan suppressed glomerular sclerosis, but did not increase the expression of SIRT1, suggesting that the renoprotective effect of olmesartan is independent of the SIRT1 pathway.
BACKGROUND: Recent studies revealed that sirtuin 1 (SIRT1) has a relation to the mechanism of transforming growth factor-beta (TGF-beta) mediated apoptosis in glomerular mesangial cells and plays an important role in blood pressure regulation. It has been suggested that SIRT1 contributes to the renoprotective effect of angiotensin receptor blocker (ARB), but this has not yet become clearly recognized. In this study, we examined the relationship between SIRT1 and the therapeutic effect of olmesartan on renal injury in nephrectomized spontaneously hypertensiverats (SHRs). METHODS: Male Wistar rats and 5/6 nephrectomized (5/6Nx) SHRs were assigned to 5 groups as follows: group A, Wistar rats; group B, Wistar rats administered high-dose olmesartan (15 mg/kg/day); group C, 5/6Nx SHRs; group D, 5/6Nx SHRs administered low-dose (3 mg/kg/day) olmesartan; and group E, 5/6Nx SHRs administered high-dose olmesartan. The drugs were administered for 12 weeks. Blood pressure and urinary protein excretion were measured every 4 weeks. Serum creatinine, glomerular sclerosis, SIRT1 mRNA level, TGF-beta mRNA level and klotho mRNA level were measured at the end of the examination. RESULTS: Systolic blood pressure, urinary protein excretion, serum creatinine and glomerular sclerosis in Wistar rats were significantly lower than that of 5/6Nx SHRs. Among 5/6Nx SHRs, high doses of olmesartan significantly decreased urinary protein excretion, serum creatinine and glomerular sclerosis compared to the non-treated and low-dose olmesartan groups. Expression of SIRT1 and klotho mRNA were significantly downregulated in 5/6Nx SHRs; however, olmesartan did not attribute to any change in gene expression. Expression of TGF-beta mRNA was significantly increased in 5/6Nx SHRs, and olmesartan did not affect the level of TGF-beta mRNA expression. CONCLUSION: Expression of SIRT1 is decreased in 5/6Nx SHRs compared to Wistar rats. Olmesartan suppressed glomerular sclerosis, but did not increase the expression of SIRT1, suggesting that the renoprotective effect of olmesartan is independent of the SIRT1 pathway.
Authors: Joseph T Rodgers; Carlos Lerin; Wilhelm Haas; Steven P Gygi; Bruce M Spiegelman; Pere Puigserver Journal: Nature Date: 2005-03-03 Impact factor: 49.962