Aberrant DNA methylation of pregnane X receptor underlies metabolic gene alterations in the diabetic kidney

Published on Apr 1, 2018in American Journal of Physiology-renal Physiology3.144
· DOI :10.1152/AJPRENAL.00390.2017
Atsushi Watanabe6
Estimated H-index: 6
(National Defense Medical College),
Atsushi Watanabe4
Estimated H-index: 4
(National Defense Medical College)
+ 11 AuthorsToshiro Fujita121
Estimated H-index: 121
(UTokyo: University of Tokyo)
Epigenetic abnormalities have been suggested to mediate metabolic memory observed in diabetic complications. We have shown that epigenetic alterations may induce persistent phenotypic changes in the proximal tubules of the diabetic kidneys. In this study, we show that pregnane X receptor (PXR), a xenobiotic nuclear receptor, is epigenetically altered and upregulated, and may have a possible function in the diabetic kidney. PXR has been shown to play a critical role in metabolic changes in obesity and diabetes; however, its distribution and function in the kidney are unknown. In the normal kidney, PXR was selectively expressed in the proximal tubular cells with demethylation in the promoter DNA. In db/db mice, significant increases in Pxr mRNA, further demethylation of DNA, and stimulatory histone marks in the promoter were observed. Epigenetic changes are likely to play a causative role in PXR induction since a DNA methyltransferase inhibitor increased PXR mRNA in cultured human proximal tubular cells. Administration of a PXR agonist increased mRNA levels of Slco2b1, a xenobiotic transporter, Rgc32, a molecule known to exert fibrotic effects in the kidney, and Pck1, a gluconeogenic enzyme, in the kidney. The expressions of these genes were inhibited by PXR siRNA in cultured proximal tubular cells. Increased mRNA levels of Slco2b1, Rgc32, and Pck1 were also observed in the kidney of db/db mice. These data indicate that PXR is upregulated in the diabetic kidney with aberrant epigenetic modifications and may modulate the course of diabetic kidney disease through the activation of these genes.
📖 Papers frequently viewed together
20 Citations
142 Citations
2 Citations
Abstract Cardiometabolic disease emerges as a worldwide epidemic and there is urgent need to understand the molecular mechanisms underlying this chronic disease. The chemical environment to which we are exposed has significantly changed in the past few decades and recent research has implicated its contribution to the development of many chronic human diseases. However, the mechanisms of how exposure to chemicals contributes to the development of cardiometabolic disease are poorly understood. Nu...
14 CitationsSource
#1Lacramioara Bintu (California Institute of Technology)H-Index: 10
#2John Yong (California Institute of Technology)H-Index: 3
Last. Michael B. Elowitz (California Institute of Technology)H-Index: 54
view all 8 authors...
Chromatin regulators play a major role in establishing and maintaining gene expression states. Yet how they control gene expression in single cells, quantitatively and over time, remains unclear. We used time-lapse microscopy to analyze the dynamic effects of four silencers associated with diverse modifications: DNA methylation, histone deacetylation, and histone methylation. For all regulators, silencing and reactivation occurred in all-or-none events, enabling the regulators to modulate the fr...
254 CitationsSource
#1Shunsaku Nakagawa (Kyoto University)H-Index: 11
#2Kumiko Nishihara (Kyoto University)H-Index: 7
Last. Satohiro Masuda (Kyoto University)H-Index: 60
view all 14 authors...
In chronic kidney disease (CKD), progressive nephron loss causes glomerular sclerosis, as well as tubulointerstitial fibrosis and progressive tubular injury. In this study, we aimed to identify molecular changes that reflected the histopathological progression of renal tubulointerstitial fibrosis and tubular cell damage. A discovery set of renal biopsies were obtained from 48 patients with histopathologically confirmed CKD, and gene expression profiles were determined by microarray analysis. The...
69 CitationsSource
#1Marpadga A. Reddy (Beckman Research Institute)H-Index: 41
#2Rama Natarajan (Beckman Research Institute)H-Index: 87
The growing epidemic of obesity and diabetes, the aging population as well as prevalence of drug abuse has led to significant increases in the rates of the closely associated acute and chronic kidney diseases, including diabetic nephropathy. Furthermore, evidence shows that parental behavior and diet can affect the phenotype of subsequent generations via epigenetic transmission mechanisms. These data suggest a strong influence of the environment on disease susceptibility and that, apart from gen...
68 CitationsSource
#1Matthew D. Schultz (UCLA: University of California, Los Angeles)H-Index: 18
#2Yupeng He (UCLA: University of California, Los Angeles)H-Index: 19
Last. Joseph R. EckerH-Index: 154
view all 19 authors...
As part of the Epigenome Roadmap Project, genome-wide maps of DNA methylation and transcriptomes together with genomic DNA sequencing of 18 different primary human tissue types from 4 individuals are presented; analysis reveals widespread differential methylation of CG sites between tissues, and the presence of non-CG methylation in adult tissues.
446 CitationsSource
#1Takeshi MarumoH-Index: 17
#2Shintaro Yagi (UTokyo: University of Tokyo)H-Index: 22
Last. Toshiro FujitaH-Index: 121
view all 12 authors...
Epigenetic mechanisms may underlie the progression of diabetic kidney disease. Because the kidney is a heterogeneous organ with different cell types, we investigated DNA methylation status of the kidney in a cell type–specific manner. We first identified genes specifically demethylated in the normal proximal tubules obtained from control db/m mice, and next delineated the candidate disease-modifying genes bearing aberrant DNA methylation induced by diabetes using db/db mice. Genes involved in gl...
58 CitationsSource
#1Xiao-Bing Cui (Louisiana State University System)H-Index: 1
#2Jun-Na Luan (Louisiana State University System)H-Index: 1
Last. Shi-You Chen (Louisiana State University System)H-Index: 1
view all 4 authors...
Obesity is an important independent risk factor for type 2 diabetes, cardiovascular diseases and many other chronic diseases. Adipose tissue inflammation is a critical link between obesity and insulin resistance and type 2 diabetes and a contributor to disease susceptibility and progression. The objective of this study was to determine the role of response gene to complement 32 (RGC-32) in the development of obesity and insulin resistance. Wild-type (WT) and RGC-32 knockout (RGC32–/–) mice were ...
29 CitationsSource
Abstract The kidneys play an important role in regulating glucose homeostasis through utilization of glucose, gluconeogenesis, and glucose reabsorption via sodium glucose co-transporters (SGLTs) and glucose transporters. The renal threshold for glucose excretion (RT G ) is increased in patients with type 2 diabetes mellitus (T2DM), possibly due to upregulation of SGLT2 and SGLT1 expression. The resulting increase in renal glucose reabsorption is thought to contribute to the maintenance of hyperg...
109 CitationsSource
#1Madhukumar Venkatesh (Albert Einstein College of Medicine)H-Index: 12
#2Subhajit Mukherjee (Albert Einstein College of Medicine)H-Index: 8
Last. Sridhar Mani (Albert Einstein College of Medicine)H-Index: 54
view all 19 authors...
Summary Intestinal microbial metabolites are conjectured to affect mucosal integrity through an incompletely characterized mechanism. Here we showed that microbial-specific indoles regulated intestinal barrier function through the xenobiotic sensor, pregnane X receptor (PXR). Indole 3-propionic acid (IPA), in the context of indole, is a ligand for PXR in vivo, and IPA downregulated enterocyte TNF-α while it upregulated junctional protein-coding mRNAs. PXR-deficient ( Nr1i2 −/− ) mice showed a di...
389 CitationsSource
#1Saki Gotoh (NIH: National Institutes of Health)H-Index: 4
#2Masahiko Negishi (NIH: National Institutes of Health)H-Index: 79
Drug activation of the human nuclear pregnane X receptor (PXR) induced gluconeogenic genes and increased glucose production. In this study, we have determined that serum- and glucocorticoid-regulated kinase 2 (SGK2) is an essential factor that mediates this PXR-regulated glucose 6-phosphatase (G6Pase) induction and glucose production. Both SGK2 and G6Pase mRNAs were increased in rifampicin-treated HepG2 cells stably expressing human PXR. Reporter and chromatin immunoprecipitation assays delineat...
21 CitationsSource
Cited By7
#1Zheng Wen (Zhengzhou University)H-Index: 1
#2Jia Guo (Zhengzhou University)H-Index: 1
Last. Zhangsuo Liu (Zhengzhou University)H-Index: 22
view all 3 authors...
Diabetic kidney disease (DKD) is one of the most common microvascular complication of both type 1 (T1DM) and type 2 diabetes mellitus (T2DM), and the leading cause of end-stage renal disease (ESRD) worldwide. Persistent inflammation and subsequent chronic fibrosis are major causes of loss of renal function, which is associated with the progression of DKD to ESRD. In fact, DKD progression is affected by a combination of genetic and environmental factors. Approximately, one-third of diabetic patie...
#1Zhilin Luan (Dalian Medical University)H-Index: 3
#2Yuanyi Wei (Dalian Medical University)H-Index: 3
Last. Xiaoyan Zhang (Dalian Medical University)H-Index: 9
view all 14 authors...
Abstract Cisplatin-induced acute kidney injury (CAKI) has been recognized as one of the most serious side effects of cisplatin. Pregnane X receptor (PXR) is a ligand-dependent nuclear receptor and serves as a master regulator of xenobiotic detoxification. Increasing evidence also suggests PXR has many other functions including the regulation of cell proliferation, inflammatory response, and glucose and lipid metabolism. In this study, we aimed to investigate the role of PXR in cisplatin-induced ...
1 CitationsSource
#1Martine Daujat-Chavanieu (University of Montpellier)H-Index: 11
#2Sabine Gerbal-Chaloin (University of Montpellier)H-Index: 30
Pregnane X receptor (PXR, NR1I2) and constitutive androstane receptor (CAR, NR1I3) are members of the nuclear receptor superfamily that mainly act as ligand-activated transcription factors. Their functions have long been associated with the regulation of drug metabolism and disposition, and it is now well established that they are implicated in physiological and pathological conditions. Considerable efforts have been made to understand the regulation of their activity by their cognate ligand; ho...
6 CitationsSource
#1Laura Smyth ('QUB': Queen's University Belfast)H-Index: 6
#2Jill Kilner ('QUB': Queen's University Belfast)H-Index: 4
Last. Amy Jayne McKnight ('QUB': Queen's University Belfast)H-Index: 29
view all 4 authors...
Genomic DNA (gDNA) is the optimal source of DNA for methylation analysis. This study compared methylation patterns in gDNA derived from blood with cell-line derived DNA (clDNA) from the same individuals. The clDNA had been generated via an Epstein-Barr virus transformation of the participant’s lymphocytes. This analysis sought to determine whether clDNA has the potential to be utilised in lieu of finite/unavailable gDNA in methylation analyses using Illumina Infinium MethylationEPIC BeadChip arr...
1 CitationsSource
#1Sonia I. VlaicuH-Index: 10
#2Alexandru Tatomir (UMB: University of Maryland, Baltimore)H-Index: 8
Last. Horea Rus (UMB: University of Maryland, Baltimore)H-Index: 43
view all 7 authors...
The response gene to complement (RGC)-32 acts as a cell cycle regulator and mediator of TGF-β effects. However, recent studies have revealed other functions for RGC-32 in diverse processes such as cellular migration, differentiation, and fibrosis. In addition to its induction by complement activation and the C5b-9 terminal complement complex, RGC-32 expression is also stimulated by growth factors, hormones, and cytokines. RGC-32 is induced by TGF-β through Smad3 and RhoA signaling and plays an i...
3 CitationsSource
#1Harvest F. Gu (CPU: China Pharmaceutical University)H-Index: 7
Kidney disease is a worldwide health crisis, while diabetes kidney disease (DKD) has become a leading cause of end stage renal disease (ESRD). DKD is a microvascular complication and occurs in 30-40% of diabetes patients. Epidemiological investigation and clinical observation on the familial clustering and heritability in DKD have implicated that genetic susceptibilities are involved in the pathogenesis. Furthermore, DKD is a progressive and long-term complication, in which epigenetic effects an...
20 CitationsSource
#2Vanessa Marchant (Austral University of Chile)H-Index: 4
Last. Sandra Rayego-MateosH-Index: 18
view all 9 authors...
The growing incidence of obesity, hypertension, and diabetes, coupled with the aging of the population, is increasing the prevalence of renal diseases in our society. Chronic kidney disease (CKD) is characterized by persistent inflammation, fibrosis, and loss of renal function leading to end-stage renal disease. Nowadays, CKD treatment has limited effectiveness underscoring the importance of the development of innovative therapeutic options. Recent studies have identified how epigenetic modifica...
28 CitationsSource