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Maintenance of Kidney Metabolic Homeostasis by PPAR Gamma.

ABSTRACT: Peroxisome proliferator-activated receptors (PPARs) are a family of nuclear hormone receptors that control the transcription of specific genes by binding to regulatory DNA sequences. Among the three subtypes of PPARs, PPARγ modulates a broad range of physiopathological processes, including lipid metabolism, insulin sensitization, cellular differentiation, and cancer. Although predominantly expressed in adipose tissue, PPARγ expression is also found in different regions of the kidney and, upon activation, can redirect metabolism. Recent studies have highlighted important roles for PPARγ in kidney metabolism, such as lipid and glucose metabolism and renal mineral control. PPARγ is also implicated in the renin-angiotensin-aldosterone system and, consequently, in the control of systemic blood pressure. Accordingly, synthetic agonists of PPARγ have reno-protective effects both in diabetic and nondiabetic patients. This review focuses on the role of PPARγ in renal metabolism as a likely key factor in the maintenance of systemic homeostasis.

SUBMITTER: Corrales P

PROVIDER: S-EPMC6073436 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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Maintenance of Kidney Metabolic Homeostasis by PPAR Gamma.

Corrales Patricia P Izquierdo-Lahuerta Adriana A Medina-Gómez Gema G

International journal of molecular sciences 20180716 7

Peroxisome proliferator-activated receptors (PPARs) are a family of nuclear hormone receptors that control the transcription of specific genes by binding to regulatory DNA sequences. Among the three subtypes of PPARs, PPARγ modulates a broad range of physiopathological processes, including lipid metabolism, insulin sensitization, cellular differentiation, and cancer. Although predominantly expressed in adipose tissue, PPARγ expression is also found in different regions of the kidney and, upon ac ...[more]

PMID: 30012954

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Project description:BackgroundPersistent fibroblast activation initiated by transforming growth factor β (TGF-β) is a fundamental event in the pathogenesis of systemic sclerosis, and its pharmacological inhibition represents a potential therapeutic strategy. The nuclear receptor, peroxisome proliferator-activated receptor γ (PPAR-γ), exerts potent fibrotic activity. The synthetic oleanane triterpenoid, 2-cyano-3,12-dioxo-olean-1,9-dien-28-oic acid (CDDO), is a PPAR-γ agonist with potential effects on TGF-β signalling and dermal fibrosis.ObjectiveTo examine the modulation of fibrogenesis by CDDO in explanted fibroblasts, skin organ cultures and murine models of scleroderma.Material and methodsThe effects of CDDO on experimental fibrosis induced by bleomycin injection or by overexpression of constitutively active type I TGF-β receptor (TgfbR1ca) were evaluated. Modulation of fibrotic gene expression was examined in human skin organ cultures. To delineate the mechanisms underlying the antifibrotic effects of CDDO, explanted skin fibroblasts cultured in two-dimensional monolayers or in three-dimensional full-thickness human skin equivalents were studied.ResultsCDDO significantly ameliorated dermal fibrosis in two complementary mouse models of scleroderma, as well as in human skin organ cultures and in three-dimensional human skin equivalents. In two-dimensional monolayer cultures of explanted normal fibroblasts, CDDO abrogated fibrogenic responses induced by TGF-β. These CDDO effects occurred via disruption of Smad-dependent transcription and were associated with inhibition of Akt activation. In scleroderma fibroblasts, CDDO attenuated the elevated synthesis of collagen. Remarkably, the in vitro antifibrotic effects of CDDO were independent of PPAR-γ.ConclusionsThe PPAR-γ agonist triterpenoid CDDO attenuates fibrogenesis by antagonistically targeting canonical TGF-β/Smad and Akt signalling in a PPAR-γ-independent manner. These findings identify this synthetic triterpenoid as a potential new therapy for the control of fibrosis.

Dataset Information

Maintenance of Kidney Metabolic Homeostasis by PPAR Gamma.

Publications

Maintenance of Kidney Metabolic Homeostasis by PPAR Gamma.

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