Attenuation of mTOR Signaling Is the Major Response Element in the Rescue Pathway of Chronic Kidney Disease in Rats

Abstract

Background: Modern lifestyle changes and the interlinking of non-communicable diseases result in the development of chronic kidney disease (CKD). While research has focused on attenuating the CKD, the role of mTOR in the progression of CKD is still unclear. Objectives: The current investigation was undertaken to study the role of mTOR-mediated signaling in CKD using Wistar male rats and adenine-induced CKD as an experimental model. Method: The animals were divided into 3 groups, representing control, CKD, and rapamycin-pretreated rats. At the end of the experimental period, blood biochemical indexes on kidney function and expression levels of fibrotic markers, including TGF-β, PAI-1, α-smooth muscle action, fibronectin, CTGF, and collagen-1, were analyzed. In addition, kidney injury markers such as kim-1, cystatin-C, NAG, and NGAL, indicating a progressive fibrotic response, were also studied. Results: The results suggest that mTOR inhibition significantly attenuated the induction of fibrosis, with restored serum creatinine and blood urea nitrogen levels. Intriguingly, the microRNA (miRNA) analysis revealed an increased expression of miR-193–5p, miR-221, miR-212, and miR-183–5p in CKD, while an increased mRNA expression of anti-inflammatory cytokines and reduced level of pS6K with attenuated miRNA was found in rapamycin-treated rats compared to the CKD animals. Conclusion: Activation of mTOR is the major responsive element with activation of miRNAs as an elementary role in the progression of kidney disease. Hence, targeting mTOR would be a possible strategy of treatment for CKD.