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 6

Principal cells and PT cells are the main target of mineralocorticoids and MRAs.

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Principal cells and PT cells are the main target of mineralocorticoids a...
(A) Overview of the tensor decomposition analysis. All rat samples were included in the analysis. (B) Sample score heatmap for decomposition of the snRNA-Seq data showing each sample and its loading score for each factor (lower panel). Colors on the right indicate sample groups. Colors in the bottom of the heatmap indicate each identified factor and its association with phenotypes. Each row represents a phenotype, and the color indicates the P value for the factor and phenotype association using univariate linear model F tests (upper panel). Two samples were filtered by the analysis. (C) Heatmaps showing the cell type gene loading scores of genes in factors 1 and 4. Some of the genes are highlighted. (D) Single-nucleus WGCNA of PC, PST, and iPT cells identified gene expression modules in cell types (top panel). The top representative genes in each cell-type–specific module are highlighted. Bubble plots indicate gene expression levels of the genes in each module in each cell type (middle panel) calculated by the average expression of all genes in a module in a specific cell type. The lower panel shows the module scores per condition for each cell type.