Figure 1. SNuc-Seq from kidneys of Pdss2^kd/kd mice reveals a podocyte-specific Mapk pathway, and treatment of mice with the Braf/Mapk-targeted compound GDC-0879 reverses kidney filter damage.

(A) UMAP visualization of single-nucleus transcriptomic profiles from three 5-month-old Pdss2^kd/kd mice (KDKD) and 3 age-matched control mice (CTRL). Cell-type clusters identified by canonical marker genes. (B) Proportions of clusters across control and Pdss2^kd/kd mice (left) with corresponding cell numbers (right). Pdss2^kd/kd-specific clusters indicated with black arrowheads. CNT, connecting tubule; CD, collecting duct; PC, principal cell; IC, intercalated cell. (C) Analysis of leading edge genes from GSEA on differentially expressed genes between control and Pdss2^kd/kd podocytes shows 3 pathway clusters: an actin cytoskeleton pathway (Actb, Actg1, Actn4, Actn1), a Mapk pathway (Raf1, Mapk1, Braf), and an ETC pathway (Uqcrq, Cox6a1, Uqcrh, Ndufs7). (D) Dot plot shows gene expression of Mapk pathway genes identified by GSEA in podocyte and PT clusters in control versus KDKD mice. (E) Urine albumin to creatinine ratio (UACR) of Pdss2^kd/kd mice treated with 100 mg/kg/d or vehicle for 14 days. n = 5 animals per condition. Two-way ANOVA, Tukey’s multiple comparison test. ***P < 0.001.