The Nuclear Receptor ESRRA Protects from Kidney Disease by Coupling Metabolism and Differentiation

Dhillon, Poonam; Park, Jihwan; Pozo, Carmen Hurtado del; Li, Lingzhi; Doke, Tomohito; Huang, Shizheng; Zhao, Juanjuan; Kang, Hyun Mi; Shrestra, Rojesh; Balzer, Michael S.; Chatterjee, Shatakshee; Prado, Patricia; Han, Seung Yub; Liu, Hongbo; Sheng, Xin; Dierickx, Pieterjan; Batmanov, Kirill; Romero, Juan Pablo; Prósper, Felipe; Li, Mingyao; Pei, Liming; Kim, Junhyong; Montserrat, Núria; Suszták, Katalin

doi:10.1016/j.cmet.2020.11.011

Cited by 96 publications

(82 citation statements)

References 66 publications

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“…These changes resemble reported transcriptional changes in kidneys after acute kidney injury (AKI) 2,[19][20][21] , suggesting that EHHADH deficiency causes kidney injury in male mouse kidneys.…”

Section: Transcriptional Activation Of Proximal Tubule Kidney Injury Signatures In Male Ehhadh Ko Kidneyssupporting

confidence: 61%

“…We then compared the DEGs identified in Ehhadh KO male kidneys with expression signatures from PT cells of three different AKI mouse models; ischemia-reperfusion injury 19 , folic acid nephropathy (FAN) 20 and unilateral ureteral obstruction (UUO) 21 (Table S1D). Genes upregulated or downregulated in the male Ehhadh KO kidneys generally changed in the same direction in the FAN and UUO models (Fig.…”

Section: Transcriptional Activation Of Proximal Tubule Kidney Injury Signatures In Male Ehhadh Ko Kidneysmentioning

confidence: 99%

“…Next, we performed cis-regulatory sequence analysis to uncover the transcriptional regulatory network underlying the transcriptional response of Ehhadh KO male mouse kidneys 18 (Table S1E). We identified enriched transcription factor (TF) motifs in the down-regulated DEGs of Ehhadh KO kidneys that mapped to known regulators of PT differentiation such as HNF1A, HNF4A, RXRA, and ESRRA 19,20,27 (Fig. 2D).…”

Section: C)mentioning

confidence: 99%

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Peroxisomal L-bifunctional Protein Deficiency Causes Male-specific Kidney Hypertrophy and Proximal Tubular Injury in Mice

et al. 2021

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Background: Proximal tubular (PT) cells are enriched in mitochondria and peroxisomes. Whereas mitochondrial fatty acid oxidation (FAO) plays an important role in kidney function by supporting the high-energy requirements of PT cells, the role of peroxisomal metabolism remains largely unknown. EHHADH, also known as L-bifunctional protein, catalyzes the second and third step of peroxisomal FAO. Methods: We studied kidneys of WT and Ehhadh KO mice on a C57BL/6N background using histology, immunohistochemistry, immunofluorescence, immunoblot, RNA-sequencing, and metabolomics. To assess the role of androgens in the kidney phenotype of Ehhadh KO mice, mice underwent orchiectomy. Results: We observed male-specific kidney hypertrophy and glomerular filtration rate reduction in adult Ehhadh KO mice. Transcriptome analysis unveiled a gene expression signature similar to PT injury in acute kidney injury mouse models. This was further illustrated by the presence of KIM-1 (kidney injury molecule-1), SOX-9, and Ki67-positive cells in the PT of male Ehhadh KO kidneys. Male Ehhadh KO kidneys had metabolite changes consistent with peroxisomal dysfunction as well as an elevation in glycosphingolipid levels. Orchiectomy of Ehhadh KO mice decreased the number of KIM-1 positive cells to WT levels. We revealed a pronounced sexual dimorphism in the expression of peroxisomal FAO proteins in mouse kidney, underlining a role of androgens in the kidney phenotype of Ehhadh KO mice. Conclusions: Our data highlight the importance of EHHADH and peroxisomal metabolism in male kidney physiology and reveal peroxisomal FAO as a sexual dimorphic metabolic pathway in mouse kidneys.

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Section: Transcriptional Activation Of Proximal Tubule Kidney Injury Signatures In Male Ehhadh Ko Kidneyssupporting

confidence: 61%

Section: Transcriptional Activation Of Proximal Tubule Kidney Injury Signatures In Male Ehhadh Ko Kidneysmentioning

confidence: 99%

Section: C)mentioning

confidence: 99%

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Peroxisomal L-bifunctional Protein Deficiency Causes Male-specific Kidney Hypertrophy and Proximal Tubular Injury in Mice

et al. 2021

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“…Transcriptome analysis of human kidney samples from CKD patients revealed that defective fatty acid oxidation (FAO) played a key role in kidney fibrosis development [ 10 ]. Recently, single-cell RNA sequencing of mouse kidney fibrotic models clarified that impaired energy metabolism (FAO and OXPHOS) coupled with poor cell differentiation of proximal tubules is a critical driver of kidney fibrosis [ 11 ••].…”

Section: Dysregulated Energy Metabolism and Mitochondrial Dysfunction In Dkdmentioning

confidence: 99%

Harnessing Metabolomics to Describe the Pathophysiology Underlying Progression in Diabetic Kidney Disease

Hasegawa

Inagi

2021

Curr Diab Rep

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Purpose of Review Diabetic kidney disease (DKD), a leading cause of end-stage kidney disease, is the result of metabolic network alterations in the kidney. Therefore, metabolomics is an effective tool for understanding its pathophysiology, finding key biomarkers, and developing a new treatment strategy. In this review, we summarize the application of metabolomics to DKD research. Recent Findings Alterations in renal energy metabolism including the accumulation of tricarboxylic acid cycle and glucose metabolites are observed in the early stage of DKD, and they finally lead to mitochondrial dysfunction in advanced DKD. Mitochondrial fission-fusion imbalance and dysregulated organelle crosstalk might contribute to this process. Moreover, metabolomics has identified several uremic toxins including phenyl sulfate and tryptophan derivatives as promising biomarkers that mediate DKD progression. Summary Recent advances in metabolomics have clarified the role of dysregulated energy metabolism and uremic toxins in DKD pathophysiology. Integration of multi-omics data will provide additional information for identifying critical drivers of DKD.

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“…Transcriptome analysis demonstrated a markedly decreased expression of key enzymes and regulators of FAO in kidney diseases [ 6 ]. Recently, through unbiased cell trajectory analyses, it revealed that differentiation of PTECs was altered in kidney disease, which was strongest and most reproducible associated with OXPHOS and FAO in tubules [ 14 ]. The first and rate-limiting component of FAO system is carnitine palmitoyltransferase 1 (CPT1).…”

Section: Introductionmentioning

confidence: 99%

CPT1α maintains phenotype of tubules via mitochondrial respiration during kidney injury and repair

Ding

et al. 2021

Cell Death Dis

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Impaired energy metabolism in proximal tubular epithelial cells (PTECs) is strongly associated with various kidney diseases. Here, we characterized proximal tubular phenotype alternations during kidney injury and repair in a mouse model of folic acid nephropathy, in parallel, identified carnitine palmitoyltransferase 1α (CPT1α) as an energy stress response accompanied by renal tubular dedifferentiation. Genetic ablation of Cpt1α aggravated the tubular injury and interstitial fibrosis and hampered kidney repair indicate that CPT1α is vital for the preservation and recovery of tubular phenotype. Our data showed that the lipid accumulation and mitochondrial mass reduction induced by folic acid were persistent and became progressively more severe in PTECs without CPT1α. Interference of CPT1α reduced capacities of mitochondrial respiration and ATP production in PTECs, and further sensitized cells to folic acid-induced phenotypic changes. On the contrary, overexpression of CPT1α protected mitochondrial respiration and prevented against folic acid-induced tubular cell damage. These findings link CPT1α to intrinsic mechanisms regulating the mitochondrial respiration and phenotype of kidney tubules that may contribute to renal pathology during injury and repair.

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The Nuclear Receptor ESRRA Protects from Kidney Disease by Coupling Metabolism and Differentiation

Cited by 96 publications

References 66 publications

Peroxisomal L-bifunctional Protein Deficiency Causes Male-specific Kidney Hypertrophy and Proximal Tubular Injury in Mice

Peroxisomal L-bifunctional Protein Deficiency Causes Male-specific Kidney Hypertrophy and Proximal Tubular Injury in Mice

Harnessing Metabolomics to Describe the Pathophysiology Underlying Progression in Diabetic Kidney Disease

CPT1α maintains phenotype of tubules via mitochondrial respiration during kidney injury and repair

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