Potential therapeutic efficacy of pachymic acid in chronic kidney disease induced in rats: role of Wnt/beta-catenin/renin-angiotensin axis

Objectives: Chronic kidney disease (CKD) is a major public health problem associated with high mortality.The therapeutic effects of pachymic in CKD management and its underlying mechanisms have not been studied. Therefore, we aimed to investigate the possible inhibitory effect of PA on renal Wnt/beta-catenin signalling in CKD. Methods: CKD was induced in rats by doxorubicin (DOX; 3.5 mg/kg i.p., twice weekly for 3 weeks). Rats were treated orally with PA (10 mg/kg/day), LOS (10 mg/kg/day) or their combination (PA + LOS) for 4 weeks starting after the last dose of DOX. Key findings: DOX-induced renal injury was characterized by high serum cystatin-C, and urine albumin/creatinine ratio, renal content of podocin and klotho were decreased. Tumour necrosis factor-alpha, interleukin-6, interleukin-1 beta, Wnt1, active beta-catenin/total beta-catenin ratio and fibronectin along with mRNA expression of RENIN, ACE and AT1 were increased in renal tissues. Treatment with either PA or LOS ameliorated all DOX-induced changes. The combined treatment was more effective in improving all changes than monotherapy. Conclusions: These results suggest a new therapeutic benefit of PA in ameliorating CKD in rats through its up-regulatory effect on renal klotho thereby preventing Wnt/beta-catenin reactivation and RAS gene expression. PA/LOS combination provided an additional inhibition of Wnt/beta-catenin signalling and its downstream targets.