Phosphocreatine attenuates diabetes-exacerbated kidney fibrosis via TGF-β/Smad and PI3K/Akt pathways in a dual rat model.

Diabetes accelerates kidney fibrosis through chronic inflammation, oxidative stress, and activation of profibrotic signaling pathways, including TGF-β/Smad and PI3K/Akt. This study investigated the renoprotective effects of phosphocreatine (PCr) in a dual rat model combining STZ-induced diabetes with unilateral ureteral obstruction (UUO)-induced renal fibrosis. PCr was administered intraperitoneally at 20 or 50 mg/kg for eight weeks, starting one-week post-UUO. Renal function, oxidative stress markers, mitochondrial bioenergetics, and inflammatory cytokines (TNF-α, IL-6) were evaluated. Histopathological changes were assessed via Masson's Trichrome, and Sirius Red staining, while protein expression of collagen I, α-SMA, TGF-β, Smad2/3, and PI3K/Akt was analyzed by Western blotting. Diabetic UUO kidneys exhibited impaired renal function, elevated oxidative stress, mitochondrial dysfunction, increased inflammatory cytokines, and upregulation of fibrotic markers along with TGF-β/Smad and PI3K/Akt signaling. PCr treatment dose-dependently ameliorated these alterations, reducing collagen deposition, restoring mitochondrial function, suppressing inflammation, and inhibiting profibrotic signaling. These findings highlight PCr as a potential multi-targeted therapeutic agent for diabetes-associated kidney fibrosis.