Quercetin enhances the renoprotective effects of phosphodiesterase inhibitors by attenuating endoplasmic reticulum stress-induced cellular apoptosis via modulation of GRP75/CHOP/Bax/Bcl2 pathway.

This study investigated the ability of quercetin (QU) alone or with sildenafil (Sild) or pentoxifylline (PTX) to modulate carbon tetrachloride (CCl4)-induced renal fibrosis in Wistar albino rats. Renal fibrosis was induced by intraperitoneal injection of CCl4 (1.5 ml/kg, three times weekly for 10 weeks). Rats received oral doses of QU (50 mg/kg once daily), PTX (50 mg/kg once daily), and Sild (10 mg/kg twice daily) separately or in combination from week 7 to week 10. CCl4 induced severe renal injury as indicated by urinary electrolytes disturbance, renal function impairment, increased oxidative stress, inflammation, up-regulation of endoplasmic reticulum (ER) stress markers (CHOP, GRP75), and apoptosis (Bax), as well as down-regulation of defense proteins (Bcl2, Nrf2, HO-1). QU, Sild, and PTX, alone or in combination, improved renal function and alleviated histological changes. The combination of QU with Sild or PTX resulted in greater renoprotection by regulating several key pathways, including reductions in ER stress, enhanced antioxidative defenses, and regulation of apoptosis. In conclusion, a combination of QU with Sild or PTX ameliorates renal fibrosis by inhibiting ER stress-induced cellular apoptosis through modulation of the GRP75/CHOP/Bax/Bcl2 and oxidative stress pathways.