Flavin containing monooxygenase 2 regulates renal tubular cell fibrosis and paracrine secretion via SMURF2 in AKI‑CKD transformation

Abstract

In the follow-up of hospitalized patients with acute kidney injury (AKI), it has been observed that 15-30% of these patients progress to develop chronic kidney disease (CKD). Impaired adaptive repair of the kidneys following AKI is a fundamental pathophysiological mechanism underlying renal fibrosis and the progression to CKD. Deficient repair of proximal tubular epithelial cells is a key factor in the progression from AKI to CKD. However, the molecular mechanisms involved in the regulation of fibrotic factor paracrine secretion by injured tubular cells remain incompletely understood. Transcriptome analysis and an ischemia-reperfusion injury (IRI) model were used to identify the contribution of flavin-containing monooxygenase 2 (FMO2) in AKI-CKD. Lentivirus-mediated overexpression of FMO2 was performed in mice. Functional experiments were conducted using TGF-β-induced tubular cell fibrogenesis and paracrine pro-fibrotic factor secretion. Expression of FMO2 attenuated kidney injury induced by renal IRI, renal fibrosis, and immune cell infiltration into the kidneys. Overexpression of FMO2 not only effectively blocked TGF secretion in tubular cell fibrogenesis but also inhibited aberrant paracrine activation of pro-fibrotic factors present in fibroblasts. FMO2 negatively regulated TGF-β-mediated SMAD2/3 activation by promoting the expression of SMAD ubiquitination regulatory factor 2 (SMURF2) and its nuclear translocation. During the transition from AKI to CKD, FMO2 modulated tubular cell fibrogenesis and paracrine secretion through SMURF2, thereby affecting the outcome of the disease.

TGF‑β/Smad signaling in chronic kidney disease: Exploring post‑translational regulatory perspectives (Review)

“…This is evidenced by the fact that the overexpression of Smurf2 has been shown to encourage the activation of the TGF-β-responsive promoter and induce EMT within human kidney cortical epithelial cells ( 107 ). Recent research has demonstrated that flavin-containing monooxygenase 2 can enhance the expression of Smurf2 and facilitate its nuclear translocation, resulting in tubular cell fibrogenesis and paracrine secretion ( 110 ). In addition, the E3 ligase, Arkadia/RNF111, regulates TGF-β signaling by degrading Smad7 ( 111 , 112 ).…”