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mTORC1 activation induced proximal tubular damage via the pentose phosphate pathway in lupus nephritis

磷酸戊糖途径 狼疮性肾炎 mTORC1型 葡萄糖-6-磷酸脱氢酶 NADPH氧化酶 癌症研究 化学 内科学 生物 内分泌学 糖酵解 脱氢酶 细胞凋亡 PI3K/AKT/mTOR通路 医学 生物化学 氧化应激 疾病
作者
Zhaomin Mao,Ying Tan,Juan Tao,Linlin Li,Feng Yu,Ming‐Hui Zhao
出处
期刊:Free Radical Biology and Medicine [Elsevier BV]
卷期号:189: 91-101 被引量:3
标识
DOI:10.1016/j.freeradbiomed.2022.07.010
摘要

More recent studies suggested that metabolic disorders could contribute to the pathogenesis of systemic lupus erythematosus (SLE) and lupus nephritis (LN). The present work aimed at identifying metabolic reprogramming in the kidney of lupus nephritis via proteomics and investigating the potential regulatory mechanism. The proteomic studies on the renal biopsies revealed that the pentose phosphate pathway (PPP) was significantly enriched in the kidneys of LN patients compared with normal controls (NCs). Immunohistochemical stanning of glucose-6-phosphate dehydrogenase (G6PD), the key rate-limiting enzyme of PPP, verify the results of proteomics. We found that G6PD was highly expressed in the kidneys of LN patients and correlated with several clinicopathological indices. The univariate Cox regression analysis (HR, 95%CI, 1.877 (1.059–3.328), P = 0.031) and Kaplan-Meier (KM) analysis (P = 0.028) suggested that high G6PD expression in the tubulointerstitial area was a risk factor for worse prognosis. Moreover, the Gene set enrichment analysis (GSEA) demonstrated that the mammalian target of rapamycin complex 1 (mTORC1) signaling pathway ranked first in the kidneys of LN patients with high G6PD expression and G6PD was co-localized with mTORC1 activation in the tubule. Immunoglobulin G (IgG) isolated from LN patients significantly activated the mTORC1 pathway and increased G6PD expression, G6PD activity, NADPH production, NADPH oxidase 2 (NOX2) expression, reactive oxygen species (ROS) production, and cell apoptosis in tubule cells in vitro. The above phenotypes were partially rescued after the addition of rapamycin or knock-down of G6PD. Overall, our study suggested that renal G6PD expression was associated with the overall enhanced disease activity and worse renal prognosis. mTORC1 activation might be involved in IgG-LN-induced tubular damage via PPP.
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