The Nuclear Receptor ESRRA Protects from Kidney Disease by Coupling Metabolism and Differentiation

Kidney disease is poorly understood because of the organ's cellular diversity. We used single-cell RNA sequencing not only in resolving differences in injured kidney tissue cellular composition but also in cell type-specific gene expression in mouse models of kidney disease. This analysis highlighted major changes in cellular diversity in kidney disease, which markedly impacted whole-kidney transcriptomics outputs. Cell type-specific differential expression analysis identified proximal tubule (PT) cells as the key vulnerable cell type. Through unbiased cell trajectory analyses, we show that PT cell differentiation is altered in kidney disease. Metabolism (fatty acid oxidation and oxidative phosphorylation) in PT cells showed the strongest and most reproducible association with PT cell differentiation and disease. Coupling of cell differentiation and the metabolism was established by nuclear receptors (estrogen-related receptor alpha [ESRRA] and peroxisomal proliferation-activated receptor alpha [PPARA]) that directly control metabolic and PT-cell-specific gene expression in mice and patient samples while protecting from kidney disease in the mouse model.

Automated summary

This study utilized single-cell RNA sequencing to investigate cellular diversity and gene expression changes in kidney disease, identifying proximal tubule cells as a key vulnerable cell type with significant impact on disease development. The study revealed a strong association between metabolism (fatty acid oxidation and oxidative phosphorylation) and proximal tubule cell differentiation and disease progression, regulated by nuclear receptors.