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Single-cell transcriptomics and chromatin accessibility profiling elucidate the kidney-protective mechanism of mineralocorticoid receptor antagonists
Amin Abedini, … , Peter Kolkhof, Katalin Susztak
Amin Abedini, … , Peter Kolkhof, Katalin Susztak
Published October 31, 2023
Citation Information: J Clin Invest. 2024;134(1):e157165. https://doi.org/10.1172/JCI157165.
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Research Article Genetics Nephrology Article has an altmetric score of 21

Single-cell transcriptomics and chromatin accessibility profiling elucidate the kidney-protective mechanism of mineralocorticoid receptor antagonists

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Abstract

Mineralocorticoid excess commonly leads to hypertension (HTN) and kidney disease. In our study, we used single-cell expression and chromatin accessibility tools to characterize the mineralocorticoid target genes and cell types. We demonstrated that mineralocorticoid effects were established through open chromatin and target gene expression, primarily in principal and connecting tubule cells and, to a lesser extent, in segments of the distal convoluted tubule cells. We examined the kidney-protective effects of steroidal and nonsteroidal mineralocorticoid antagonists (MRAs), as well as of amiloride, an epithelial sodium channel inhibitor, in a rat model of deoxycorticosterone acetate, unilateral nephrectomy, and high-salt consumption–induced HTN and cardiorenal damage. All antihypertensive therapies protected against cardiorenal damage. However, finerenone was particularly effective in reducing albuminuria and improving gene expression changes in podocytes and proximal tubule cells, even with an equivalent reduction in blood pressure. We noted a strong correlation between the accumulation of injured/profibrotic tubule cells expressing secreted posphoprotein 1 (Spp1), Il34, and platelet-derived growth factor subunit b (Pdgfb) and the degree of fibrosis in rat kidneys. This gene signature also showed a potential for classifying human kidney samples. Our multiomics approach provides fresh insights into the possible mechanisms underlying HTN-associated kidney disease, the target cell types, the protective effects of steroidal and nonsteroidal MRAs, and amiloride.

Authors

Amin Abedini, Andrea Sánchez-Navaro, Junnan Wu, Konstantin A. Klötzer, Ziyuan Ma, Bibek Poudel, Tomohito Doke, Michael S. Balzer, Julia Frederick, Hana Cernecka, Hongbo Liu, Xiujie Liang, Steven Vitale, Peter Kolkhof, Katalin Susztak

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Figure 8

iPT cell signature can classify disease severity in human diabetic and hypertensive kidney tissue samples.

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iPT cell signature can classify disease severity in human diabetic and h...
(A) Correlations with fibrosis between SPP1, IL34, and PDGFB in microdissected human kidney tubule samples. The x axis represents normalized (log transcripts per million [TPM]) gene expression, and the y axis represents the fibrosis score (log-transformed). Each dot indicates 1 sample. Spearman’s test and correlation coefficient (r) as well as the regression line are shown in each plot. *P < 0.05, **P < 0.01, and ***P < 0.0001 (B) Schematic overview of the experiments. The homologous genes for the iPT gene signature in rats were used to cluster 991 human kidney microdissected tubules. (C) The 3 distinct human kidney clusters were identified on the basis of the iPT signature using hierarchical clustering. The 3 main clusters in the dendrogram are shown in different colors. Graphs represent the clinical information on samples from the 3 clusters. The χ2 test for nonparametric and 1-way ANOVA for parametric data were used for statistical comparisons. Error bars indicate the SD.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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