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

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

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 5

Genome-wide gene expression changes in whole-kidney samples from DOCA-treated rats given MRAs.

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Genome-wide gene expression changes in whole-kidney samples from DOCA-tr...
(A) Number of DEGs between DOCA-treated and control groups by bulk RNA-Seq analysis. (B) Enrichment of genes showing lower expression with DOCA in PST cells in the snRNA-Seq and snATAC-Seq data sets. The color scheme of the heatmap is based on z score distribution. Each row represents a gene, and each column represents a cell type. Yellow indicates cell-type–enriched genes. (C) Expression of 25 genes showing higher or lower expression levels in DOCA versus control groups in the bulk RNA-Seq data set. The color scheme of the heatmap is based on z score distribution. Each row represents a gene, and each column represents a rat sample. Black and red colors indicate control and DOCA-treated rats, respectively. (D) Volcano plot of DEGs between DOCA and control groups in the bulk RNA-Seq data. (E) Cell-type expression (snRNA-Seq and snATAC-Seq) of the top upregulated DEGs in DOCA versus control groups identified in the bulk analysis. The color scheme of the heatmap is based on z score distribution; yellow indicates higher expression, while blue indicates lower expression. Each row represents a gene, and each column represents a cell type.