PDE5 inhibitor LW1646 improves kidney fibrosis by alleviating ER stress and maintaining mitochondrial homeostasis

Renal fibrosis is the terminal pathological manifestation of most chronic kidney diseases. The phosphodiesterase type 5 (PDE5) inhibitors have shown therapeutic potentials in a wide array of chronic conditions. LW1646 is a newly identified inhibitor with high specificity and potency against PDE5. The current study aims to investigate the therapeutic effects of LW1646 on renal fibrosis and its underlying mechanisms. mRNA and protein expression level of PDE5 was elevated in renal cortex of mice with unilateral ureter obstruction for seven days (7UUO). LW1646 effectively suppressed pro-fibrotic responses in TGF-β1-stimulated HK-2 cells as well as in mice with 7UUO-induced renal fibrosis. Genetic deletion or knockdown of Pde5a produced similar antifibrotic benefits. Mechanistically, both PDE5 inhibition with LW1646 and Pde5a knockout alleviated ER stress and mitigated mitochondrial dysfunction, as evidenced by restored mitochondrial biogenesis, suppression of excessive fragmentation, preservation of membrane potential, and reduction of oxidative stress. Further investigation revealed that ER stress-driven mitochondrial injury involved augmented mitochondria associated membrane (MAM) formation, characterized by increased expression of the hallmark IP3R1-GRP75-VDAC1 complex. This enhanced interaction facilitated excessive calcium transfer from the ER to mitochondria, culminating in mitochondrial calcium overload. PDE5 inhibition effectively suppressed MAM formation and reduced mitochondrial calcium accumulation, thereby maintaining mitochondrial homeostasis under fibrotic stress. Collectively, these findings identify activation of cGMP-PKG signaling by LW1646 as a promising therapeutic pathway for renal fibrosis through suppression of ER stress and stabilization of mitochondrial homeostasis.