title: Combination therapy with telmisartan and spironolactone alleviates L-NAME exacerbated nephrosclerosis with an increase in PPAR-gamma and decrease in TGF-beta(1).
abstract: To investigate whether the receptor blockades of angiotensin II type 1 and aldosterone receptors can prevent renal tissue injury in relation to the renal tissue mRNA levels of peroxisome proliferation-activated receptors-gamma (PPAR-gamma) and transforming growth factor-beta (1) (TGF-beta(1)) in spontaneously hypertensive rats (SHR) given N(G)-nitro-L-arginine methyl ester (L-NAME), which is considered a model of malignant hypertension. This study was performed in 5 groups of 17-week-old male SHR treated for 3 weeks as follows: group 1, control; group 2, L-NAME (50 mg/L in drinking); group 3, L-NAME plus aldosterone antagonist, spironolactone (SPRL, 100 mg/kg/day); group 4, L-NAME plus angiotensin II type 1 receptor blocker, telmisartan (TELM, 3 mg/kg/day); group 5, L-NAME plus combination therapy (COMB) with low-dose TELM (1 mg/kg/day) and SPRL (100 mg/kg/day). Urinary protein excretion and the glomerular injury score were significantly reduced in the SPRL, TELM, and COMB groups as compared with the L-NAME group, while significant blood pressure reduction was observed only in the TELM group. In the TELM and COMB groups, the perivascular cell infiltration and fibrosis area were significantly reduced together with the PPAR-gamma mRNA increase and TGF- beta(1) mRNA decrease. The urinary excretion of nitric oxides was significantly recovered and the wall to lumen ratio of the interlobular artery was significantly reduced only in the COMB group compared with the L-NAME group. Combined administration of 1 mg/kg/day telmisartan and 100 mg/kg/day spironolactone is thought to be effective in alleviating hypertensive renal injuries independently of blood pressure changes. The anti-inflammatory and antifibrotic effects due to PPAR-gamma activation and TGF-beta(1) inhibition may participate in the renoprotection of this combination therapy.
authors.affiliation: Department of Hypertension and Cardiorenal Disease, Dokkyo Medical University, Tochigi, Japan.
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Takahashi
authors.forename: Hidehiko
authors.initials: H
authors.lastname: Ono
authors.forename: Yuko
authors.initials: Y
authors.lastname: Ono
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Ishimitsu
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Matsuoka
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000008:administration & dosage*; D000818:Animals; D001562:Benzimidazoles / Q000008:administration & dosage*; D001565:Benzoates / Q000008:administration & dosage*; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D006974:Hypertension, Malignant / Q000150:complications* / Q000188:drug therapy / Q000378:metabolism; D008297:Male; D000451:Mineralocorticoid Receptor Antagonists / Q000008:administration & dosage*; D019331:NG-Nitroarginine Methyl Ester; D009400:Nephrosclerosis / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR; D013148:Spironolactone / Q000008:administration & dosage*; D000077333:Telmisartan; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001565:Benzoates; D000451:Mineralocorticoid Receptor Antagonists; D047495:PPAR gamma; D012333:RNA, Messenger; D053773:Transforming Growth Factor beta1; D013148:Spironolactone; D000077333:Telmisartan; D019331:NG-Nitroarginine Methyl Ester