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Peroxisome proliferator-activated receptor ?-dependent renoprotection of murine kidney by irbesartan.

ABSTRACT: Activation of renal peroxisome proliferator-activated receptor ? (PPAR?) is renoprotective, but there is no safe PPAR? activator for patients with chronic kidney disease (CKD). Studies have reported that irbesartan (Irbe), an angiotensin II receptor blocker (ARB) widely prescribed for CKD, activates hepatic PPAR?. However, Irbe's renal PPAR?-activating effects and the role of PPAR? signalling in the renoprotective effects of Irbe are unknown. Herein, these aspects were investigated in healthy kidneys of wild-type (WT) and Ppara-null (KO) mice and in the murine protein-overload nephropathy (PON) model respectively. The results were compared with those of losartan (Los), another ARB that does not activate PPAR?. PPAR? and its target gene expression were significantly increased only in the kidneys of Irbe-treated WT mice and not in KO or Los-treated mice, suggesting that the renal PPAR?-activating effect was Irbe-specific. Irbe-treated-PON-WT mice exhibited decreased urine protein excretion, tubular injury, oxidative stress (OS), and pro-inflammatory and apoptosis-stimulating responses, and they exhibited maintenance of fatty acid metabolism. Furthermore, the expression of PPAR? and that of its target mRNAs encoding proteins involved in OS, pro-inflammatory responses, apoptosis and fatty acid metabolism was maintained upon Irbe treatment. These renoprotective effects of Irbe were reversed by the PPAR? antagonist MK886 and were not detected in Irbe-treated-PON-KO mice. These results suggest that Irbe activates renal PPAR? and that the resultant increased PPAR? signalling mediates its renoprotective effects.

SUBMITTER: Harada M

PROVIDER: S-EPMC6331013 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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Peroxisome proliferator-activated receptor α-dependent renoprotection of murine kidney by irbesartan.

Harada Makoto M Kamijo Yuji Y Nakajima Takero T Hashimoto Koji K Yamada Yosuke Y Shimojo Hisashi H Gonzalez Frank J FJ Aoyama Toshifumi T

Clinical science (London, England : 1979) 20160805 21

Activation of renal peroxisome proliferator-activated receptor α (PPARα) is renoprotective, but there is no safe PPARα activator for patients with chronic kidney disease (CKD). Studies have reported that irbesartan (Irbe), an angiotensin II receptor blocker (ARB) widely prescribed for CKD, activates hepatic PPARα. However, Irbe's renal PPARα-activating effects and the role of PPARα signalling in the renoprotective effects of Irbe are unknown. Herein, these aspects were investigated in healthy ki ...[more]

PMID: 27496805

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Project description:Our aim was to investigate if the peroxisome proliferator-activated receptor (PPAR)-gamma agonist pioglitazone modulates inflammation through PPARalpha mechanisms.The thiazolidinediones (TZDs) pioglitazone and rosiglitazone are insulin-sensitizing PPARgamma agonists used to treat type 2 diabetes (T2DM). Despite evidence for TZDs limiting inflammation and atherosclerosis, questions exist regarding differential responses to TZDs. In a double-blinded, placebo-controlled 16-week trial among recently diagnosed T2DM subjects (n = 34), pioglitazone-treated subjects manifested lower triglycerides and lacked the increase in soluble vascular cell adhesion molecules (sVCAM)-1 evident in the placebo group. Previously we reported PPARalpha but not PPARgamma agonists could repress VCAM-1 expression. Since both triglyceride-lowering and VCAM-1 repression characterize PPARalpha activation, we studied pioglitazone's effects via PPARalpha.Pioglitazone effects on known PPARalpha responses--ligand binding domain activation and PPARalpha target gene expression--were tested in vitro and in vivo, including in wild-type and PPARalpha-deficient cells and mice, and compared with the effects of other PPARgamma (rosiglitazone) and PPARalpha (WY14643) agonists.Pioglitazone repressed endothelial TNFalpha-induced VCAM-1 messenger ribonucleic acid expression and promoter activity, and induced hepatic IkappaBalpha in a manner dependent on both pioglitazone exposure and PPARalpha expression. Pioglitazone also activated the PPARalpha ligand binding domain and induced PPARalpha target gene expression, with in vitro effects that were most pronounced in endothelial cells. In vivo, pioglitazone administration modulated sVCAM-1 levels and IkappaBalpha expression in wild-type but not PPARalpha-deficient mice.Pioglitazone regulates inflammatory target genes in hepatic (IkappaBalpha) and endothelial (VCAM-1) settings in a PPARalpha-dependent manner. These data offer novel mechanisms that may underlie distinct TZD responses.

Dataset Information

Peroxisome proliferator-activated receptor ?-dependent renoprotection of murine kidney by irbesartan.

Publications

Peroxisome proliferator-activated receptor α-dependent renoprotection of murine kidney by irbesartan.

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