Single-cell transcriptomics reveals how TRPC6 inhibition alters renal cell composition and gene expression in CKD. The study uncovers a novel endothelial subpopulation (ECRIN), highlights key inflammatory and fibrotic pathways, and identifies a Prnp-driven network linked to fibrosis resolution, offering mechanistic insight into TRPC6 as a potential therapeutic target in CKD. Abstract Chronic kidney disease (CKD) is characterized by persistent inflammation and tubulointerstitial fibrosis leading to end-stage renal disease. Transient receptor potential canonical 6 (TRPC6) channel inhibition mitigates tubular injury and renal fibrosis in murine models of unilateral ureteral obstruction (UUO) and 2-month chronic post–ischemia-reperfusion injury (2m post-I/R). Through integrated analysis of single-cell-RNA-sequencing (scRNA-Seq) data from UUO mice treated with the selective TRPC6 inhibitor SH045, here the renoprotective cell composition and cell type-specific transcriptional programs are defined. We explored translational aspects by conducting an in-depth scRNA-Seq analysis of kidney samples from patients with CKD. These results reveal global transcriptional shifts with a dramatic diversification of inflammatory cells, endothelial cells and fibroblasts. Notably, a distinct subpopulation of novel endothelial cells is delineated, which is termed ECRIN, that regulate inflammatory networks implicating VEGF and GAS signaling pathways. The data also indicates that inhibition of TRPC6 channels triggers a Prnp transcription factor regulatory network, which contributes to the alleviation of renal fibrosis. The key findings are supported at the protein level by immunofluorescence and western blot analysis. We observed similar patterns in the chronic 2m postI/R injury model. These findings provide novel insights into the potential therapeutic benefits of TRPC6 inhibition in CKD.

Transient Receptor Potential Canonical 5 (T RP C5) and T RP C6 channels play critical physiological roles in various cell types. Their involvement in numerous disease progression mechanisms has led...

FSGS is the most common primary glomerular lesion that causes kidney failure in the US. FSGS results from injury or loss of glomerular visceral epithelial cells (i.e. podocytes). Pathogenic variants in TRPC6 can cause FSGS through dysregulated calcium conductance and associated disturbances in podocyte physiology. Here, we describe a 5-generation kindred with FSGS caused by a novel compound C-terminal TRPC6 mutation. Analysis of patient-specific iPSC-derived podocytes and glomerular capillary wall-on-a-chip systems revealed that the compound variants disrupt TRPC6 protein structure, intermolecular interactions, and membrane localization. Combined therapy with Sildenafil and Losartan ameliorated these disturbances compared to conventional immunosuppressive treatment. ### Competing Interest Statement S. Musah is an inventor on a patent for stem cell differentiation into podocytes and establishment of a glomerulus chip. S. Musah is also an inventor on a pending patent for engineering in vivo-like models of kidney tissues.

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【Elife】<AbstractText>The slow-intrinsic-pacemaker dopaminergic (DA) neurons originating in the ventral tegmental area (VTA) are...