ACSS2 gene variants determine kidney disease risk by controlling de novo lipogenesis in kidney tubules
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
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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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 7

Changes in DNL gene expression in the kidneys of patients with CKD.

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Changes in DNL gene expression in the kidneys of patients with CKD. (A) ...
(A) Relative gene expression z scores for ACSS2, NR1H3, NR1H4, SREBF1, SCAP, PLIN2, PLIN5, ACACAB, ACLY, and FASN in healthy human kidney snRNA-Seq data. PEC, parietal epithelial cells; Mes, mesangial cells; IC_A, intercalated cells A; IC_B, intercalated cells B. (B) Gene expression z score for ACSS2, NR1H3, NR1H4, SREBF1, SCAP, PLIN2, PLIN5, ACACAB, ACLY, and FASN from human CKD kidney snRNA-Seq in various kidney cell types. (C) ISH of human ACSS2 and LRP2 in healthy and CKD human kidneys. Original magnification, ×20 (scale bar: 20 μm) and ×60 (scale bar: 10 μm). (D) Quantification of RNA ISH (n = 4). (E) ISH of mouse Acss2 and Lrp2 in healthy mouse kidney samples. Original magnification, ×20 (scale bar: 20 μm) and ×60 (scale bar: 10 μm). (F) Immunofluorescence images of ACSS2 expression in healthy human kidneys. LTL identifies the PT segment. Scale bars: 20 μm and 10 μm (inset). (G) Immunofluorescence images of FASN expression in healthy human kidneys. LTL identifies the PT segment. Scale bars: 20 μm and 10 μm (inset). (H) Immunoblots showing SCAP, FASN, PLIN2, NLRP3, and GSDMD expression in healthy and CKD kidneys (n = 6). (I) Quantification of immunoblots. Data were normalized to GAPDH and are presented as the mean ± SEM. In the healthy group, the sixth sample was excluded from statistical analysis because of its disease-like characteristics. The first sample from the healthy group was excluded from the SCAP analysis. Only 3 healthy samples and 4 CKD samples were included in the GSMD statistical analysis due to high variability. *P < 0.05 and **P < 0.01, by 1-way ANOVA after Tukey’s multiple-comparison test (D and I). The protein marker was cropped from all blots but is presented in the full blots file.