Ciglitazone, a peroxisome proliferator-activated receptor gamma inducer, ameliorates renal preglomerular production and activity of angiotensin II and thromboxane A2 in glycerol-induced acute renal failure.
Peroxisome proliferator-activated receptor gamma (PPARgamma), a nuclear transcription factor, modulates vascular responses to angiotensin II (AII) or thromboxane A(2) (TxA(2)) via regulation of their gene/receptor. Increased vasoconstriction and deteriorating renal function in glycerol-induced acute renal failure (ARF) may be attributed to down-regulation of PPARgamma. In this study, we investigated the effect of ciglitazone (CG), a PPARgamma inducer, on AII and TxA(2) production and activity in glycerol-induced ARF. Vascular responses to AII or 9,11-dideoxy-11alpha,9alpha-epoxymethano prostaglandin F(2alpha) (U46619), a TxA(2) mimetic, were determined in preglomerular vessels following induction of ARF with glycerol. Renal damage and function were assessed in CG-treated (9 nmol/kg for 21 days) rats. PPARgamma protein expression and activity, which were significantly lower in ARF rats, were enhanced by CG (26 and 30%). CG also increased PPARgamma mRNA by 67 +/- 6%, which was reduced in ARF. In ARF, there was significant tubular necrosis and apoptosis, a 5-fold increase in proteinuria and a 2-fold enhancement in vasoconstriction to AII and U46619. CG reduced proteinuria (49 +/- 3%), enhanced Na(+) (124 +/- 35%) and creatinine excretion (92 +/- 25%), markedly diminished tubular necrosis, and reduced ARF-induced increase in AII (40 +/- 3%) and TxA(2) (39 +/- 2%) production, the attending increase in vasoconstriction to AII (36 +/- 2%) and U46619 (50 +/- 11%), and the increase in angiotensin receptor-1 (AT(1)) (23 +/- 3%) or thromboxane prostaglandin (TP) receptor (13 +/- 1%). CG reduced free radical generation by 55 +/- 14% while elevating nitrite excretion (65 +/- 13%). Our results suggest that enhanced activity of AII and TxA(2), increased AT(1) or TP receptor expression, and renal injury in glycerol-induced ARF are consequent to down-regulation of PPARgamma gene. CG ameliorated glycerol-induced effects through maintaining PPARgamma gene.
Yousefipour
Zivar
Z
Center for Cardiovascular Diseases, Texas Southern University, 3100 Cleburne Avenue, Houston, TX 77004, USA.
Hercule
Hantz
H
Truong
Luan
L
Oyekan
Adebayo
A
Newaz
Mohammad
M
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D058186:Acute Kidney Injury / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D000804:Angiotensin II / Q000097:blood / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D003404:Creatinine / Q000652:urine; D015237:Dinoprost / Q000031:analogs & derivatives / Q000097:blood; D015870:Gene Expression / Q000187:drug effects; D005990:Glycerol / Q000633:toxicity; D007004:Hypoglycemic Agents / Q000494:pharmacology / Q000627:therapeutic use; D007678:Kidney Glomerulus / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism; D009573:Nitrites / Q000652:urine; D047495:PPAR gamma / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D011507:Proteinuria / Q000517:prevention & control / Q000652:urine; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D044244:Receptors, Thromboxane A2, Prostaglandin H2 / Q000378:metabolism; D012077:Renal Artery / Q000187:drug effects / Q000502:physiology; D012964:Sodium / Q000652:urine; D045162:Thiazolidinediones / Q000494:pharmacology* / Q000627:therapeutic use; D013928:Thromboxane A2 / Q000819:agonists / Q000378:metabolism*; D013929:Thromboxane B2 / Q000652:urine; D014661:Vasoconstriction / Q000187:drug effects
D007004:Hypoglycemic Agents; D009573:Nitrites; D047495:PPAR gamma; D044140:Receptor, Angiotensin, Type 1; D044244:Receptors, Thromboxane A2, Prostaglandin H2; D045162:Thiazolidinediones; D000804:Angiotensin II; C075750:8-epi-prostaglandin F2alpha; D009569:Nitric Oxide; D013929:Thromboxane B2; D013928:Thromboxane A2; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D012964:Sodium; D003404:Creatinine; D015237:Dinoprost; D005990:Glycerol; C039671:ciglitazone