ArticleResearch square2025
Downregulation of Akt induces proximal tubule epithelial cell apoptosis via Foxo-1-BIM pathway in proteinuric states.
Article in Research square, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Proteinuria is a widely utilized surrogate marker in clinical practice for its predictive and prognostic value. The mechanistic link between proteinuria and progression remains elusive. Proximal tubule epithelial cells(PTEC) retrieve albumin in the glomerular filtrate via receptor mediated endocytosis facilitated by megalin-cubilin complex. We reported that cell-survival protein, Akt phosphorylates cargo binding endocytic adaptor protein to megalin, disabled-2(Dab2). We hypothesize that downregulation of Akt signaling as a result of overwhelmed endocytic machinery in albumin overload is linked to PTEC apoptosis in proteinuric states. We show that cell culture and animal model of albumin overload inhibited phosphorylation of Akt in association with apoptosis in PTEC. Chemical inhibition and overexpression of Akt by constitutively active Akt plasmid exacerbated and alleviated apoptosis respectively in response to albumin overload in PTEC. Mouse with targeted inhibition of Akt1 and Akt2 in PTEC (Akt1/2lox/loxSGLT2cre) displayed perturbed albumin endocytosis at baseline. Albumin overload in Akt1/2
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