PPARγ Dependence of Cyclosporine–Isoprenaline Renovascular Interaction: Roles of Nitric Oxide Synthase and Heme Oxygenase

Abstract

We previously showed that cyclosporine (CSA) impairs renal vasodilations caused by β-adrenoceptor activation. This study investigated whether the peroxisome proliferator-activated receptor gamma (PPARγ) and related nitric oxide synthase (NOS)/heme oxygenase (HO) signaling mediates the CSA-β-adrenoceptor interaction. The vasodilatory response elicited by a bolus injection of isoprenaline (1 μmole) in phenylephrine-preconstricted perfused kidneys of rats was reduced after prior infusion of zinc protoporphyrin IX (ZnPP, HO inhibitor) or GW9662 (PPARγ antagonist), suggesting the involvement of PPARγ and HO-derived CO in the isoprenaline response. In contrast, the inhibition of NOS activity by N-nitro-l-arginine methyl ester had no effect on isoprenaline responses. CSA (5 μM) significantly attenuated isoprenaline vasodilations, an effect that was abolished in the presence of GW9662 and accentuated by ZnPP. Also, supplementation with the PPARγ agonist pioglitazone or with l-arginine or hemin, substrates for NOS and HO, respectively, eliminated the unfavorable effect of CSA on isoprenaline vasodilations. The protection conferred by pioglitazone against CSA-evoked attenuation of isoprenaline vasodilations was maintained in N-nitro-l-arginine methyl ester-treated kidneys and disappeared after treatment with ZnPP or GW9662. In conclusion, the activation of the HO/CO/PPARγ cascade is probably the cellular mechanism that underlies the beneficial effect of pioglitazone on the CSA-isoprenaline interaction. Further, the facilitation of the HO/CO or NOS/NO pathway seems to offset this harmful effect of CSA.

Additive Renoprotection by Pioglitazone and Fenofibrate against Inflammatory, Oxidative and Apoptotic Manifestations of Cisplatin Nephrotoxicity: Modulation by PPARs

“…A total of 9 groups of rats (n = 8 each) were employed and randomly assigned to receive one of the following regimens: (i) control (saline, 1 ml /kg/day), (ii) DMSO (1 ml /kg/day), (iii) cisplatin (a single i.p. dose of 5 mg/kg) [ 18 ], (iv) cisplatin + pioglitazone (PPARγ agonist, 2.5 mg/kg/day, orally) [ 19 ], (v) cisplatin + fenofibrate (PPARα agonist, 100 mg/kg/day, orally) [ 20 ], (vi) cisplatin + pioglitazone + fenofibrate, (vii) cisplatin + pioglitazone + GW9662 (PPARγ antagonist, 1 mg/kg/day i.p) [ 21 ], (viii) cisplatin + fenofibrate + GW6471 (PPARα antagonist, 1 mg/kg/day, i.p) [ 22 ], (ix) cisplatin + thalidomide (12.5 mg/kg/day, i.p) [ 23 ]. Thalidomide was dissolved in DMSO while all other drugs were dissolved in saline.…”

Interference with AGEs formation and AGEs-induced vascular injury mediates curcumin vascular protection in metabolic syndrome

“…Additionally, evidence obtained from our laboratory 41 and others 42 links NOS-derived NO to vasodilation caused by the activation of cholinergic sites as well as by several other vasodilator stimuli. These multiple cellular events have been shown to be distinctly affected by vasculotoxic insults and corrective measures 40,43,44 . More studies are apparently needed to precisely identify the cellular mechanism(s) of the NO-dependent vasodilatory action of CUR.…”

Impairment of Nitric Oxide Synthase but Not Heme Oxygenase Accounts for Baroreflex Dysfunction Caused by Chronic Nicotine in Female Rats

“…The dynamics and interplay between NOS and HO and their enzymatic products is now of magnificent importance in the understanding of various disease states and potential therapeutic strategies [49]–[51]. Paradoxically, contrasting biological effects for the two systems have also been described [52].…”