FBXW7 Protects against Diabetic Nephropathy by Targeting Metadherin for Ubiquitin Degradation

Diabetic nephropathy (DN), a critical complication of diabetes, is characterized by progressive renal function impairment and fibrosis development. F-box and WD repeat domain-containing 7 (FBXW7), an E3 ubiquitin ligase, is recognized for its role in metabolic disorders; however, its specific functions and mechanisms in DN remain incompletely understood. This study aimed to clarify the role of FBXW7 in the pathogenesis of DN.

Mouse tubular epithelial cells (mTECs) cultured under hyperglycemic conditions were used. FBXW7 overexpression was induced in the kidneys of db/db mice and in mTECs to evaluate its effects on renal fibrosis and related molecular pathways. The interaction between FBXW7 and metadherin (Mtdh) was examined by using co-immunoprecipitation and Western blotting techniques.

FBXW7 expression was found to be significant reduced in the kidneys of DN patients and db/db mice. Overexpression of FBXW7 markedly improved albuminuria, blood urea nitrogen, uric acid levels, and renal fibrosis in db/db mice. Additionally, FBXW7 was shown to inhibit high glucose-induced fibrosis in mTECs through a mechanism involving the ubiquitin-mediated degradation of Mtdh, a protein known to promote fibrosis. Suppression of Mtdh via FBXW7 overexpression was also linked to inactivation of TGF-β/Smad3 signaling in DN.

These findings highlight the protective role of FBXW7 in DN by downregulating Mtdh and indicate that FBXW7 represents a promising therapeutic target for DN.