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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, PPAR? modulates a broad range of physiopathological processes, including lipid metabolism, insulin sensitization, cellular differentiation, and cancer. Although predominantly expressed in adipose tissue, PPAR? expression is also found in different regions of the kidney and, upon activation, can redirect metabolism. Recent studies have highlighted important roles for PPAR? in kidney metabolism, such as lipid and glucose metabolism and renal mineral control. PPAR? is also implicated in the renin-angiotensin-aldosterone system and, consequently, in the control of systemic blood pressure. Accordingly, synthetic agonists of PPAR? have reno-protective effects both in diabetic and nondiabetic patients. This review focuses on the role of PPAR? 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:BACKGROUND:The renal tubules, which have distant metabolic features and functions in different segments, reabsorb >99% of approximately 180?l of water and 25,000?mmol of Na?+?daily. Defective metabolism in renal tubules is involved in the pathobiology of kidney diseases. However, the mechanisms underlying the metabolic regulation in renal tubules remain to be defined. METHODS:We quantitatively compared the proteomes of the isolated proximal tubules (PT) and distal tubules (DT) from C57BL/6 mouse using tandem mass tag (TMT) labeling-based quantitative mass spectrometry. Bioinformatics analysis of the differentially expressed proteins revealed the significant differences between PT and DT in metabolism pathway. We also performed in vitro and in vivo assays to investigate the molecular mechanism underlying the distant metabolic features in PT and DT. FINDINGS:We demonstrate that the renal proximal tubule (PT) has high expression of lipid metabolism enzymes, which is transcriptionally upregulated by abundantly expressed PPAR?/?. In contrast, the renal distal tubule (DT) has elevated glycolytic enzyme expression, which is mediated by highly expressed c-Myc. Importantly, PPAR? transcriptionally enhances the protease iRhom2 expression in PT, which suppresses EGF expression and secretion and subsequent EGFR-dependent glycolytic gene expression and glycolysis. PPAR? inhibition reduces iRhom2 expression and increases EGF and GLUT1 expression in PT in mice, resulting in renal tubule hypertrophy, tubulointerstitial fibrosis and damaged kidney functions, which are rescued by 2-deoxy-d-glucose treatment. INTERPRETATION:These findings delineate instrumental mechanisms underlying the active lipid metabolism and suppressed glycolysis in PT and active glycolysis in DT and reveal critical roles for PPARs and c-Myc in maintaining renal metabolic homeostasis. FUND: This work was supported by the National Natural Science Foundation of China (grants 81572076 and 81873932; to Q.Z.), the Applied Development Program of the Science and Technology Committee of Chongqing (cstc2014yykfB10003; Q.Z.), the Program of Populace Creativities Workshops of the Science and Technology Committee of Chongqing (Q.Z.), the special demonstration programs for innovation and application of techniques (cstc2018jscx-mszdX0022) from the Science and Technology Committee of Chongqing (Q.Z.).

Project description:Cellular damage produced by conditions generating oxidative stress have far-reaching implications in human disease that encompass, but are not restricted to aging, cardiovascular disease, type 2 diabetes, airway inflammation/asthma, cancer, and metabolic syndrome including visceral obesity, insulin resistance, fatty liver disease, and dyslipidemia. Although there are numerous sources and cellular targets of oxidative stress, this review will highlight literature that has investigated downstream consequences of oxidatively-induced DNA damage in both nuclear and mitochondrial genomes. The presence of such damage can in turn, directly and indirectly modulate cellular transcriptional and repair responses to such stressors. As such, the persistence of base damage can serve as a key regulator in coordinated gene-response cascades. Conversely, repair of these DNA lesions serves as both a suppressor of mutagenesis and by inference carcinogenesis, and as a signal for the cessation of ongoing oxidative stress. A key enzyme in all these processes is 8-oxoguanine DNA glycosylase (OGG1), which, via non-catalytic binding to oxidatively-induced DNA damage in promoter regions, serves as a nucleation site around which changes in large-scale regulation of inflammation-associated gene expression can occur. Further, the catalytic function of OGG1 can alter the three-dimensional structure of specialized DNA sequences, leading to changes in transcriptional profiles. This review will concentrate on adverse deleterious health effects that are associated with both the diminution of OGG1 activity via population-specific polymorphic variants and the complete loss of OGG1 in murine models. This mouse model displays diet- and age-related induction of metabolic syndrome, highlighting a key role for OGG1 in protecting against these phenotypes. Conversely, recent investigations using murine models having enhanced global expression of a mitochondrial-targeted OGG1 demonstrate that they are highly resistant to diet-induced disease. These data suggest strategies through which therapeutic interventions could be designed for reducing or limiting adverse human health consequences to these ubiquitous stressors.

Dataset Information

Maintenance of Kidney Metabolic Homeostasis by PPAR Gamma.

Publications

Maintenance of Kidney Metabolic Homeostasis by PPAR Gamma.

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