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Regulatory role of the mTOR signaling pathway in autophagy and mesangial proliferation in IgA nephropathy

Yexin Liu,Bin Leng,Ming Xia,Di Liu,X. Tan,Guochun Chen,Liyu He,Chang Wang,Xuejing Zhu,Hong Liu

Published 2024 in Zhong nan da xue xue bao. Yi xue ban = Journal of Central South University. Medical sciences

ABSTRACT

Objective IgA nephropathy (IgAN) is the most common primary glomerular disease in China, but its pathogenesis remains unclear. This study aims to explore the regulatory role of the mammalian target of rapamycin (mTOR) signaling pathway in autophagy and mesangial proliferation during renal injury in IgA. Methods The activity of mTOR and autophagy was evaluated in kidney samples from IgAN patients and in an IgAN mouse model induced by oral bovine serum albumin and carbon tetrachloride (CCl4) injection. mTOR inhibitors (rapamycin) and activators [bpV(phen)] were administered to the IgAN mouse model to observe the effects of mTOR on autophagy and renal lesions. In human mesangial cells treated with polymeric IgA1 (p-IgA1) and mTOR modulators, the expression and distribution of cell cycle proteins were assessed, along with the effects of mTOR on mesangial cell proliferation and autophagy. Results Increased mTOR activity and decreased autophagy were observed in kidney tissues from IgAN patients and the mouse model, as evidenced by elevated phosphorylated mTOR (p-mTOR) levels and reduced LC3 expression. In the IgAN mouse model, rapamycin inhibited mTOR, restored autophagy, reduced mesangial IgA deposition, alleviated mesangial cell proliferation, and decreased proteinuria (all P<0.05). In contrast, bpV(phen) activated mTOR, further suppressed autophagy, exacerbated kidney damage, and increased proteinuria (all P<0.05). In vitro, p-IgA1 induced mesangial cell proliferation and inhibited autophagy, effects that were reversed by rapamycin and aggravated by bpV(phen) (all P<0.05). mTOR regulated mesangial cell proliferation by altering cell cycle distribution, with rapamycin inducing G1 phase arrest and bpV(phen) promoting cell cycle progression. Additionally, cyclinD1 expression in renal cortex was up-regulated in the IgAN mouse model, further increased by bpV(phen), and reduced by rapamycin (all P<0.05). Conclusion Inhibition of the mTOR signaling pathway enhances renal autophagy, reduces mesangial cell proliferation, and improves renal injury in IgAN.

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