Losartan ameliorates renal interstitial fibrosis through metabolic pathway and Smurfs-TGF-β/Smad

Area of Science:

• Nephrology
• Molecular Biology
• Metabolomics

Background:

• Renal fibrosis, a common endpoint for chronic kidney diseases, is driven by complex pathways including inflammation, oxidative stress, and metabolic dysfunction.
• Epithelial-mesenchymal transition (EMT) in renal tubular cells is a critical mechanism underlying renal fibrosis.
• Losartan, an Angiotensin II (ANG II) receptor antagonist, is known for its vasodilatory effects.

Purpose of the Study:

• To investigate the therapeutic effects of losartan on renal fibrosis in a mouse model of Unilateral Ureteral Obstruction (UUO).
• To explore the impact of losartan on the transforming growth factor-beta (TGF-β)/Smad signaling pathway and metabolomic profiles in the context of renal fibrosis.

Main Methods:

• Establishment of a UUO model in male C57BL/6J mice.
• Administration of losartan at doses of 10, 20, and 30 mg/kg/d for 28 consecutive days.
• Analysis of serum metabolic spectrum, renal function, histological changes (tubulointerstitial injury, collagen deposition), and molecular markers (Smurf2, Smurf1, TβR-I, P-Smad2/3) related to TGF-β/Smad signaling and EMT.

Main Results:

• Losartan treatment significantly ameliorated UUO-induced abnormalities in serum metabolic profiles and improved overall renal function.
• Histological analysis revealed that losartan reduced tubulointerstitial dilation and collagen deposition, thereby mitigating renal tubular-interstitial injury and fibrosis.
• Losartan promoted the nuclear expression of Smurf2 and Smurf1, E3 ubiquitin ligases, leading to the degradation of TGF-β1 type I receptor (TβR-I) and phosphorylated Smad2/3 (P-Smad2/3), consequently inhibiting renal tubular epithelial cell EMT.

Conclusions:

• Losartan effectively reduces renal fibrosis in a mouse UUO model.
• The antifibrotic effects of losartan are mediated through the regulation of the TGF-β/Smad pathway and metabolic alterations via ubiquitination.
• Losartan demonstrates potential as a therapeutic agent for mitigating renal fibrosis by targeting EMT and associated molecular pathways.