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Loss of renal tubular G9a benefits acute kidney injury by lowering focal lipid accumulation via CES1.

ABSTRACT: Surgery-induced renal ischemia and reperfusion (I/R) injury and nephrotoxic drugs like cisplatin can cause acute kidney injury (AKI), for which there is no effective therapy. Lipid accumulation is evident following AKI in renal tubules although the mechanisms and pathological effects are unclear. Here, we report that Ehmt2-encoded histone methyltransferase G9a is upregulated in patients and mouse kidneys after AKI. Renal tubular specific knockout of G9a (Ehmt2^Ksp ) or pharmacological inhibition of G9a alleviates lipid accumulation associated with AKI. Mechanistically, G9a suppresses transcription of the lipolytic enzyme Ces1; moreover, G9a and farnesoid X receptor (FXR) competitively bind to the same promoter regions of Ces1. Ces1 is consistently observed to be downregulated in the kidney of AKI patients. Pharmacological inhibition of Ces1 increases lipid accumulation, exacerbates renal I/R-injury and eliminates the beneficial effects on AKI observed in Ehmt2^Ksp mice. Furthermore, lipid-lowering atorvastatin and an FXR agonist alleviate AKI by activating Ces1 and reducing renal lipid accumulation. Together, our results reveal a G9a/FXR-Ces1 axis that affects the AKI outcome via regulating renal lipid accumulation.

SUBMITTER: Yang D

PROVIDER: S-EPMC10240209 | biostudies-literature | 2023 Jun

REPOSITORIES: biostudies-literature

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Loss of renal tubular G9a benefits acute kidney injury by lowering focal lipid accumulation via CES1.

Yang Dong D Fan Yu Y Xiong Mingrui M Chen Yuchen Y Zhou Yihao Y Liu Xikai X Yuan Yangmian Y Wang Qing Q Zhang Yu Y Petersen Robert B RB Su Hua H Yue Junqiu J Zhang Chun C Chen Hong H Huang Kun K Zheng Ling L

EMBO reports 20230412 6

Surgery-induced renal ischemia and reperfusion (I/R) injury and nephrotoxic drugs like cisplatin can cause acute kidney injury (AKI), for which there is no effective therapy. Lipid accumulation is evident following AKI in renal tubules although the mechanisms and pathological effects are unclear. Here, we report that Ehmt2-encoded histone methyltransferase G9a is upregulated in patients and mouse kidneys after AKI. Renal tubular specific knockout of G9a (Ehmt2<sup>Ksp</sup> ) or pharmacological ...[more]

PMID: 37042626

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Dataset Information

Loss of renal tubular G9a benefits acute kidney injury by lowering focal lipid accumulation via CES1.

Publications

Loss of renal tubular G9a benefits acute kidney injury by lowering focal lipid accumulation via CES1.

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