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Renoprotective effects of telmisartan in the 5/6 nephrectomised rats

Pharmacokinetics and Non-Clinical Safety Department, Kawanishi Pharma Research Institute, Nippon Boehringer Ingelheim Co., Ltd., 3-10-1 Yato, Kawanishi, Japan, tsunenari{at}kaw.boehringer-ingelheim.com

Tsuyoshi Ohmura

Project Coordination Group, Kawanishi Pharma Research Institute, Nippon Boehringer Ingelheim Co., Ltd., 3-10-1 Yato, Kawanishi, Japan

Randolph Seidler

Corporate Deptartment R&D, Boehringer Ingelheim Animal Health GmbH, Binger Str. 173, Ingelheim, Germany

Motohiko Chachin

Medical Affairs Department Medical Development Division, Nippon Boehringer Ingelheim Co., Ltd., 3-10-1 Yato, Kawanishi, Japan

Toshihiro Hayashi

Drug Safety Management Department, Medical Development Division, Nippon Boehringer Ingelheim Co., Ltd., 3-10-1 Yato, Kawanishi, Japan

Ayako Konomi

Molecular and Cellular Biology, Kawanishi Pharma Research Institute, Nippon Boehringer Ingelheim Co., Ltd., 3-10-1 Yato, Kawanishi, Japan

Takehisa Matsumaru

Pharmacokinetics and Non-Clinical Safety Department, Kawanishi Pharma Research Institute, Nippon Boehringer Ingelheim Co., Ltd., 3-10-1 Yato, Kawanishi, Japan

Toshiyuki Sumida

Clinical Research Department, Medical Development Division, Nippon Boehringer Ingelheim Co., Ltd., 3-10-1 Yato, Kawanishi, Japan

Naoyuki Hayashi

Clinical Research Department, Medical Development Division, Nippon Boehringer Ingelheim Co., Ltd., 3-10-1 Yato, Kawanishi, Japan

Yoshiharu Horie

Medical Data Service Department, Medical Development Division, Nippon Boehringer Ingelheim Co., Ltd., 3-10-1 Yato, Kawanishi, Japan

The purpose of this study was to investigate the renoprotective effect of telmisartan on the advanced stages of nephropathy in rats with 5/6 nephrectomy (5/6 Nx).Telmisartan was orally administered for 12 weeks to rats that previously underwent 5/6 Nx or sham operations. After completion of the administration period, the degree of renal injury was examined histopathologically using indices of glomerulosclerosis and lesions of the renal tubule and interstitium.An immunohistochemical staining for transforming growth factor—beta (TGF-β1) was also performed. The suppression of urinary protein was statistically significant in surviving animals dosed with telmisartan.The enalapril group's urinary protein was also significantly suppressed for these same parameters in surviving animals. Histopathologically, telmisartan significantly decreased the progression of glomerulosclerosis and the interstitial cell infiltration at all doses tested. As assessed by immunohistochemical staining the TGF-β1 reactivity in the glomerular tissue tended to decrease in the telmisartan group when compared to the vehicle group. Thus, the progressive Thus, telmisartan ameliorates the progressive nephropathy in the remaining kidney after 5/6 Nx by non-haemodynamic as well as antihypertensive actions of the drug. pharmacological properties of telmisartan, clinical studies have been conducted to evaluate the clinical effectiveness and safety of telmisartan on diabetic nephropathy in patients with type 2 diabetes. It has been reported that telmisartan arrested progressive renal dysfunction in hypertensive patients with early-stage diabetic nephropathy. Makino et al.⁸ reported the effectiveness of this drug therapy in suppressing the progression of nephropathy in type 2 diabetic patients with or without hypertension, without serious safety concerns. Remuzzi and Remuzzi⁹ reviewed the potential protective effects of telmisartan on renal function deterioration and suggested that telmisartan may effectively ameliorate renal dysfunction in patients affected by the metabolic syndrome. In addition, telmisartan also showed renoprotective effects in some animal models: spontaneously hypertensive rats (SHR), ¹⁰ as well as the hypertensive diabetic model that combines SHR with streptozotocininduced diabetes.¹¹ Ohmura et al.¹² investigated the mechanism of the renoprotective effect of telmisartan using obese Zucker diabetic rats. Ciclosporin A-induced nephropathy in pigs was attenuated by telmisartan without any reduction of blood pressure (BP).¹³ This animal data suggested that the suppressive effect on the progression of nephropathy might be due to both haemodynamic and non-haemodynamic action(s) of the drug.

Key Words: fibrosis • vessel • kidney • angiotensin • TGF-β

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Journal of Renin-Angiotensin-Aldosterone System, Vol. 8, No. 2, 93-100 (2007)
DOI: 10.3317/jraas.2007.017


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