ACSS2 gene variants determine kidney disease risk by controlling de novo lipogenesis in kidney tubules
Dhanunjay Mukhi, … , Kathryn E. Wellen, Katalin Susztak
Dhanunjay Mukhi, … , Kathryn E. Wellen, Katalin Susztak
Published December 5, 2023
Citation Information: J Clin Invest. 2024;134(4):e172963. https://doi.org/10.1172/JCI172963.
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Research Article Genetics Nephrology

ACSS2 gene variants determine kidney disease risk by controlling de novo lipogenesis in kidney tubules

Abstract

Worldwide, over 800 million people are affected by kidney disease, yet its pathogenesis remains elusive, hindering the development of novel therapeutics. In this study, we used kidney-specific expression of quantitative traits and single-nucleus open chromatin analysis to show that genetic variants linked to kidney dysfunction on chromosome 20 target the acyl-CoA synthetase short-chain family 2 (ACSS2). By generating ACSS2-KO mice, we demonstrated their protection from kidney fibrosis in multiple disease models. Our analysis of primary tubular cells revealed that ACSS2 regulated de novo lipogenesis (DNL), causing NADPH depletion and increasing ROS levels, ultimately leading to NLRP3-dependent pyroptosis. Additionally, we discovered that pharmacological inhibition or genetic ablation of fatty acid synthase safeguarded kidney cells against profibrotic gene expression and prevented kidney disease in mice. Lipid accumulation and the expression of genes related to DNL were elevated in the kidneys of patients with fibrosis. Our findings pinpoint ACSS2 as a critical kidney disease gene and reveal the role of DNL in kidney disease.

Authors

Dhanunjay Mukhi, Lingzhi Li, Hongbo Liu, Tomohito Doke, Lakshmi P. Kolligundla, Eunji Ha, Konstantin Kloetzer, Amin Abedini, Sarmistha Mukherjee, Junnan Wu, Poonam Dhillon, Hailong Hu, Dongyin Guan, Katsuhiko Funai, Kahealani Uehara, Paul M. Titchenell, Joseph A. Baur, Kathryn E. Wellen, Katalin Susztak

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Figure 3

Kidney ACSS2 expression correlates with changes in genes in DNL.

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Kidney ACSS2 expression correlates with changes in genes in DNL. (A) Bio...
(A) Biochemical functions of ACSS2. (B) Immunoblots of H3K27ac and H3 protein levels in total histones extracted from kidneys of WT and Acss2–/– mice subjected to UUO or sham surgery (left). Quantification of H3K27ac levels by ImageJ (right). (C) Transcript levels of Acox1, Acox2, Cpt1a, and Cpt2 in kidneys of WT (n = 6) and Acss2–/– (n = 7) mice with and without UUO. (D) FAO experimental scheme. (E) FAO rate in WT (n = 6) and Acss2–/– (n = 7) mice with and without UUO surgery. (F) Transcript levels of Hmgcs1, Hmgcr, and Fdps in kidneys of WT (n = 6) and Acss2–/– (n = 7) mice with and without UUO surgery. (G) Total cholesterol in whole kidneys of WT (n = 5) and Acss2–/– (n = 7) mice following UUO. (H) Transcript levels of Scap and Srebp1 in kidneys of WT (n = 6) and Acss2–/– (n = 7) mice following UUO. (I) Transcript levels of Fasn and Acaca in kidneys of WT (n = 6) and Acss2–/– (n = 7) mice following UUO. (J) Immunoblots of FASN and GAPDH expression in whole kidneys of WT and Acss2–/– mice with UUO. (K) Measurement of DNL. (L) DNL rate in WT (n = 3) and Acss2–/– (n = 4) mice with and without UUO. (M) Transcript levels of Plin2 in kidneys of WT (n = 6) and Acss2–/– (n = 7) mice with UUO. (N) Kidney TG levels in WT (n = 6) and Acss2–/– (n = 7) mice with UUO. (O) Oil Red O staining in kidneys of WT and Acss2–/– mice with UUO. Scale bars: 10 μm. Data are presented as the mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001, by 1-way ANOVA after Tukey’s multiple-comparison test (B–N). The protein marker was cropped from all blots but is presented in the full blots file.