Renal mTORC1 activation is associated with disease activity and prognosis in lupus nephritis

Abstract

Objective: This study was initiated to evaluate mammalian target of rapamycin (mTOR) activation in renal tissue of LN patients.

Methods: This retrospective study included 187 LN patients, 20 diabetic nephropathy (DN) patients, 10 minimal change disease (MCD) patients and 10 normal controls (NCs). Seven of 187 LN patients had repeated renal biopsies. mTORC1/2 activation was evaluated by immunohistochemistry and multiplexed immunofluorescence. The association of mTORC1/2 activation with the clinicopathologic indices and prognostic outcomes was analysed among 187 LN patients. Proteomics was performed in renal biopsies of 20 LN patients. Proteomics was employed to comprehensively evaluate the impact of mTOR activation on intrarenal gene expression.

Results: mTORC1/2 was significantly activated in podocytes, mesangial cells, endothelial cells and tubular epithelial cells of LN patients as compared with those with MCD or NC. The glomerular mTORC1 activation was higher in LN patients compared with DN patients. mTORC1, but not mTORC2, activation strongly correlated with serum albumin, complement C3, proteinuria and the following pathological biomarkers of LN: crescent formation, interstitial inflammation and fibrosis. Moreover, mTORC1 activation was identified as a prognostic marker in LN patients. Bioinformatic analyses of proteomics and immunohistochemical data unveiled increased complement activation, antigen presentation and phagocytosis in LN patients with mTORC1 activation.

Conclusion: Renal mTORC1 activation could be a biomarker to reveal disease activity and predict clinical prognosis in LN patients.

Keywords: bioinformatics; lupus nephritis; mTOR; proteomics; rapamycin.