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Podocyte-Specific Deletion of STAT3 in Krüppel-Like Factor 4-Related Experimental Podocytopathy
Yogesh Gowthaman1, Chelsea C Estrada1,2, Joseph Kim1
1Division of Nephrology, Department of Medicine, Stony Brook University, Stony Brook, New York.
Journal of the American Society of Nephrology : JASN
|August 29, 2025
Abstract
No abstract available in PubMed .
Insights
Targeting STAT3 signaling in podocytes prevents kidney damage caused by Krüppel-like factor 4 (Klf4) loss. This approach halts podocyte loss, parietal cell activation, and focal segmental glomerulosclerosis (FSGS) development, preserving kidney function.
Area of Science:
- Nephrology
- Molecular Biology
- Genetics
Background:
- Podocyte loss and parietal epithelial cell activation are key features in various glomerulonephritis subtypes and focal segmental glomerulosclerosis (FSGS).
- Krüppel-like factor 4 (Klf4) loss specifically in podocytes triggers aberrant glomerular STAT3 activation, leading to podocyte depletion, parietal cell proliferation, and FSGS.
- While systemic STAT3 inhibition showed promise, the intrinsic role of podocyte STAT3 in mediating Klf4 loss effects remained unclear.
Purpose of the Study:
- To investigate whether inhibiting STAT3 signaling specifically within podocytes can prevent the FSGS phenotype induced by Klf4 deficiency.
- To elucidate the direct contribution of podocyte-intrinsic STAT3 activation to the pathogenesis of Klf4-deficiency-driven FSGS.
Main Methods:
- Generation and characterization of mice with concurrent conditional knockdown of Stat3 and Klf4 in podocytes (Klf4ΔPodStat3ΔPod).
- Analysis of gene expression arrays from human kidney biopsies (Nephroseq) and bulk RNA-seq data (NEPTUNE) to assess STAT3 signaling in glomerular diseases.
- Utilizing scRNA-seq-based deconvolution to determine cell-specific STAT3 gene expression in FSGS and control samples.
Main Results:
- Klf4ΔPodStat3ΔPod mice showed no significant podocyte loss, parietal cell activation, FSGS lesions, albuminuria, or kidney dysfunction compared to Klf4ΔPod mice.
- These mice also exhibited reduced glomerular myofibroblasts and restored overall survival.
- Human kidney biopsies with renal vasculitis revealed enriched STAT3 signaling genes, negatively correlating with eGFR, with podocytes showing higher expression of these genes.
Conclusions:
- Podocyte-specific inhibition of STAT3 signaling is sufficient to counteract the detrimental effects of Klf4 loss.
- This targeted inhibition prevents FSGS development, including podocyte loss, parietal cell activation, albuminuria, and kidney failure.
- The findings highlight podocyte STAT3 as a critical mediator in Klf4-deficiency-induced kidney disease.
