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Discovery of kidney disease targets using multimodal human podocyte injury models

ABSTRACT: Podocyte injury is a hallmark of chronic kidney disease (CKD), but whether different injury signals perturb unified or distinct molecular targets remains unclear. Using human induced pluripotent stem cell (hiPSC)-derived podocytes, we modeled cellular injury via exposure to diabetic, inflammatory, chemical toxin, biomechanical, and infectious stressors. Transcriptomic analysis revealed both shared and unique changes in gene expression across injury modes. While drug-induced injuries triggered broader transcriptional responses, conserved pathways related to lysosome function, RNA metabolism, and immune activation were identified across models. Importantly, we discovered that NEU1, CD82, ABI3BP, and ADAM17 as targets of human podocyte injury. We confirmed enrichment of these targets in kidney disease patient biopsies, underscoring their in vivo relevance and potential as therapeutic targets. These findings highlight the value of human-relevant experimental models and provide insight into podocyte injury responses, offering a framework for future precision medicine approaches.

ORGANISM(S): Homo sapiens

PROVIDER: GSE302890 | GEO | 2026/04/02

REPOSITORIES: GEO

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Project description:Background: Testican-2 is a podocyte-derived glycoprotein encoded by SPOCK2. Circulating levels of testican-2 are associated with less glomerulosclerosis and better kidney prognosis, but its biological function in the podocyte is unknown. Methods: We studied the protective effect of testican-2 on immortalized cultured human podocytes and in mice treated with adriamycin. We used immunoprecipitation-mass spectrometry to identify binding partners of testican-2 and Bio-Layer Interferometry to characterize these protein-protein interactions. Using global Spock2 knockout mice, we assessed the impact of testican-2 deficiency in models of podocyte injury and also tested whether exogenous testican-2 confers podocyte protection in these testican-2 deficient mice. Finally, we analyzed testican-2 expression in human kidney biopsy samples. Results: Testican-2 reduced reduces adriamycin-induced podocyte injury in cultured human podocytes and mice. Vitronectin is a strong binding partner for testican-2, and testican-2 inhibited inhibits the interaction between vitronectin and integrin αVβ3, an important effector of podocyte injury. Consistent with this, testican-2 administration reduced reduces activation of integrin β3 in injured podocytes. Further, Spock2 deficiency increased increases susceptibility to podocyte injury due to adriamcyin and streptozotocin induced diabetes, as determined by albuminuria, foot process effacement, nephrin expression and WT1-positive podocyte number. Importantly, exogenous testican-2 circulated circulates to the kidney, bound binds to vitronectin, reduced reduces vitronectin-integrin β3 interaction, and reduced reduces podocyte injury in Spock2 deficient mice. Finally, glomerular testican-2 expression was is reduced in human focal segmental glomerulosclerosis and diabetic kidney disease, but not tubulointerstitial nephropathy. Conclusions: These findings identify a potential mechanism for testican-2 mediated kidney protection and highlight an opportunity to therapeutically target the podocyte’s interaction with its extracellular matrix.

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Discovery of kidney disease targets using multimodal human podocyte injury models

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