Single-cell and high-resolution spatial profiling of podocytopathies reveals core mechanisms of podocyte injury.

Authors

Jianbo Qing, Yiting Zhao, Xiao Wang, Linnan Bai, Xinni Wang, Lei Zhou, Ruipeng Wei, Xinyu Huang, Jiaying Hu, Yimiao Ma, Mingjing Gao, Junnan Wu

Published in

Science advances. Volume 12. Issue 30. Pages eadw9707. Jul 24, 2026. Epub Jul 24, 2026.

Abstract

Podocytes (PODs) play a critical role in maintaining glomerular filtration function, and their injury is a key driver of progressive podocytopathies (PCPs). Despite their clinical importance, the molecular and spatial mechanisms underlying POD injury remain poorly understood. We generated a single-nucleus RNA sequencing (snRNA-seq) and high-resolution spatial transcriptomic (ST) dataset from kidney tissues of patients with five major PCP subtypes. Our analysis revealed distinct molecular signatures among PCP subtypes, injury-related cytoskeletal alterations, and POD-centered microenvironmental features associated with clinical outcomes. Through integrative analysis, we found PDE4DIP as a previously unrecognized regulator of the POD cytoskeleton. Functional experiments through in vitro and in vivo gene editing demonstrated that PDE4DIP maintains cytoskeletal integrity by scaffolding with AKAP9 and activating RAS-ERK and AKT signaling. Its expression correlated with renal function and prognosis. This study provides the comprehensive snRNA-seq and high-resolution ST atlas of PCPs, offering a valuable resource for understanding POD injury and identifying potential therapeutic targets.

PMID:
42497253
Bibliographic data and abstract were imported from PubMed on 25 Jul 2026.

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