Lysyl oxidase-like 2 inhibition ameliorated podocyte fibrosis by inhibiting transforming growth factor-beta signaling under high-glucose conditions

Background Lysyl oxidase-like 2 (LOXL2) has been implicated in tissue fibrosis; however, its role in diabetic podocyte injury remains unclear. This study aimed to investigate the contribution of LOXL2 to fibrotic signaling in podocytes under high-glucose conditions and identify its downstream molecular pathways. Methods LOXL2 expression was examined in the glomeruli of patients with diabetes using immunofluorescence staining. Human podocytes were cultured under normal or high-glucose conditions, and LOXL2 was silenced using short hairpin RNA. The gene and protein expression of fibrotic markers, autophagy-related proteins, and key signaling molecules were assessed using quantitative real-time polymerase chain reaction and western blotting. Results LOXL2 expression was markedly elevated in the glomeruli of patients with diabetes, particularly in podocytes. In vitro, high-glucose levels significantly upregulated LOXL2 and TGF-β messenger RNA expression in podocytes. LOXL2 knockdown suppressed TGF-β expression and reduced the protein levels of collagen I and α-smooth muscle actin. Furthermore, the phosphorylation of Smad2 and expression of Smad4 decreased in LOXL2-deficient cells, indicating that LOXL2 promotes fibrosis via the transforming growth factor-beta (TGF-β)/Smad pathway. In contrast, the LOXL2 knockdown did not significantly affect the expression of autophagy markers (p62, Beclin-1, and LC3A/B) or activation of the p38 MAPK pathway. Conclusion LOXL2 is upregulated in diabetic podocytes and contributes to hyperglycemia-induced fibrosis by activating the TGF-β/Smad signaling pathway. These findings suggest that LOXL2 may serve as a potential therapeutic target for preventing or attenuating podocyte injury in patients with diabetic nephropathy.