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Androgen Receptor-Driven RASSF3 Upregulation Promotes CKD Progression by Inhibiting Gαs/Gq Activity to Mediate Metabolic Reprogramming [DT]

ABSTRACT: Male sex is a risk factor for Chronic Kidney Disease (CKD), but the underlying mechanism is not yet clear. Given the well-established central role of TGF-β in CKD, we hypothesize it reprograms AR’s transcriptional network, shifting AR’s kidney function from healthy to pathogenic. Transcriptomic profiling identified RASSF3 as a critical downstream target of DHT and TGF-β1, upregulated in kidneys from male CKD patients and mice but not females. Tubule-specific Rassf3 knockout in mice prolonged survival and protected against CKD models, whereas its overexpression exerted opposite effects. Mechanistically, RASSF3 binds Gα subunits Gq and Gαs, accelerating their GTP-to-GDP transition (active to inactive) to suppress their activity—an interaction that drives kidney tubule metabolic reprogramming and exacerbates kidney injury and CKD progression. GTPase-deficient Gq/Gαs mutants or Gq/Gαs knockout abolished RASSF3-mediated metabolic reprogramming, confirming dependence on Gq/Gαs GTPase activity. AR transcriptionally upregulates RASSF3 via interaction with SP1 (a TGF-β downstream target). Importantly, δ-tocopherol binds RASSF3’s Ras-associating domain, inhibiting its activity and alleviating CKD. Our study uncovers the molecular basis of AR-driven CKD sexual dimorphism, elucidates mechanisms linking AR to kidney metabolic dysregulation, and identifies RASSF3 as a novel CKD therapeutic target.

ORGANISM(S): Homo sapiens

PROVIDER: GSE336445 | GEO | 2026/07/02

REPOSITORIES: GEO

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Androgen Receptor-Driven RASSF3 Upregulation Promotes CKD Progression by Inhibiting Gαs/Gq Activity to Mediate Metabolic Reprogramming [R3]

Project description:Male sex is a risk factor for Chronic Kidney Disease (CKD), but the underlying mechanism is not yet clear. Given the well-established central role of TGF-β in CKD, we hypothesize it reprograms AR’s transcriptional network, shifting AR’s kidney function from healthy to pathogenic. Transcriptomic profiling identified RASSF3 as a critical downstream target of DHT and TGF-β1, upregulated in kidneys from male CKD patients and mice but not females. Tubule-specific Rassf3 knockout in mice prolonged survival and protected against CKD models, whereas its overexpression exerted opposite effects. Mechanistically, RASSF3 binds Gα subunits Gq and Gαs, accelerating their GTP-to-GDP transition (active to inactive) to suppress their activity—an interaction that drives kidney tubule metabolic reprogramming and exacerbates kidney injury and CKD progression. GTPase-deficient Gq/Gαs mutants or Gq/Gαs knockout abolished RASSF3-mediated metabolic reprogramming, confirming dependence on Gq/Gαs GTPase activity. AR transcriptionally upregulates RASSF3 via interaction with SP1 (a TGF-β downstream target). Importantly, δ-tocopherol binds RASSF3’s Ras-associating domain, inhibiting its activity and alleviating CKD. Our study uncovers the molecular basis of AR-driven CKD sexual dimorphism, elucidates mechanisms linking AR to kidney metabolic dysregulation, and identifies RASSF3 as a novel CKD therapeutic target.

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