Telmisartan prevents the progression of renal injury in daunorubicin rats with the alteration of angiotensin II and endothelin-1 receptor expression associated with its PPAR-γ agonist actions.
Angiotensin II (Ang II) receptor blocker (ARB) suppresses the progression of kidney disease. However, there is limited information regarding the nephroprotective effect of ARB in daunorubicin (DNR)-induced nephrotoxicity in rats. We examined the alteration of the renal Ang II and endothelin-1 (ET-1) receptor expression and the action of telmisartan, an ARB, on DNR-induced nephrotoxicity. Sprague-Dawley rats were treated with a cumulative dose of 9 mg/kg DNR (i.v.). Telmisartan was administered orally every day for 6 weeks. DNR rats showed nephrotoxicity as evidenced by worsening renal function, which was evaluated by measuring protein in urine, levels of urea and creatinine in serum, lipid profiles, malondialdehyde level, and the glutathione peroxidase activity in kidney tissue. These changes were reversed by treatment with telmisartan, which resulted in significant improvement in renal function. Furthermore, telmisartan increased nephrin protein expression, and down-regulated renal expression of Ang II and its receptor Ang II type I. Renal protein expressions of ET-1 and its receptor ET-receptor type A were increased in DNR rats, and treatment with telmisartan attenuated these increased expressions. Telmisartan mediated a further increase in the expression of peroxisome proliferator-activated receptor-γ (PPAR-γ). In addition, the expressions of cyclooxygenase-2 and cellular adhesion molecules were increased in DNR rats, which were attenuated by telmisartan. In conclusion, telmisartan has a protective effect on DNR-induced nephrotoxicity through Ang II and ET-1, with the alteration of their receptor expressions, which is associated with its anti-inflammatory and anti-oxidant effects at least in part through PPAR-γ agonistic actions.
Arozal
Wawaimuli
W
Department of Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Niigata University of Pharmacy and Applied Life Sciences, 265-1 Higashijima Akiha-ku, Niigata City 956-8603, Japan.
Watanabe
Kenichi
K
Veeraveedu
Punniyakoti T
PT
Ma
Meilei
M
Thandavarayan
Rajarajan A
RA
Sukumaran
Vijayakumar
V
Suzuki
Kenji
K
Kodama
Makoto
M
Aizawa
Yoshifusa
Y
D000804:Angiotensin II / Q000187:drug effects / Q000378:metabolism; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D000903:Antibiotics, Antineoplastic / Q000633:toxicity; D000975:Antioxidants / Q000494:pharmacology; D001562:Benzimidazoles / Q000494:pharmacology*; D001565:Benzoates / Q000494:pharmacology*; D003630:Daunorubicin / Q000633:toxicity*; D005786:Gene Expression Regulation / Q000187:drug effects; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D007674:Kidney Diseases / Q000139:chemically induced / Q000517:prevention & control*; D007677:Kidney Function Tests; D008297:Male; D047495:PPAR gamma / Q000819:agonists; D051381:Rats; D017207:Rats, Sprague-Dawley; D044022:Receptor, Endothelin A / Q000187:drug effects / Q000378:metabolism; D000077333:Telmisartan
D047228:Angiotensin II Type 1 Receptor Blockers; D000893:Anti-Inflammatory Agents; D000903:Antibiotics, Antineoplastic; D000975:Antioxidants; D001562:Benzimidazoles; D001565:Benzoates; D047495:PPAR gamma; D044022:Receptor, Endothelin A; D000804:Angiotensin II; D000077333:Telmisartan; D003630:Daunorubicin