Glomerular mTORC1 activation was associated with podocytes to endothelial cells communication in lupus nephritis.

ABSTRACT

OBJECTIVE: This study was initiated to evaluate the mammalian target of the rapamycin (mTOR) signalling pathway involved in renal endothelial-podocyte crosstalk in patients with lupus nephritis (LN). METHODS: We compared the kidney protein expression patterns of 10 patients with LN with severe endothelial-podocyte injury and 3 patients with non-severe endothelial-podocyte injury on formalin-fixed paraffin-embedded kidney tissues using label-free liquid chromatography-mass spectrometry for quantitative proteomics analysis. Podocyte injury was graded by foot process width (FPW). The severe group was referred to patients with both glomerular endocapillary hypercellularity and FPW >1240 nm. The non-severe group included patients with normal endothelial capillaries and FPW in the range of 619~1240 nm. Gene Ontology (GO) enrichment analyses were performed based on the protein intensity levels of differentially expressed proteins in each patient. An enriched mTOR pathway was selected, and the activation of mTOR complexes in renal biopsied specimens was further verified in 176 patients with LN. RESULTS: Compared with those of the non-severe group, 230 proteins were upregulated and 54 proteins were downregulated in the severe group. Furthermore, GO enrichment analysis showed enrichment in the 'positive regulation of mTOR signalling' pathway. The glomerular activation of mTOR complex 1 (mTORC1) was significantly increased in the severe group compared with the non-severe group (p=0.034), and mTORC1 was located in podocytes and glomerular endothelial cells. Glomerular activation of mTORC1 was positively correlated with endocapillary hypercellularity (r=0.289, p<0.001) and significantly increased in patients with both endocapillary hypercellularity and FPW >1240 nm (p<0.001). CONCLUSIONS: Glomerular mTORC1 was highly activated in patients with both glomerular endocapillary hypercellularity and podocyte injury, which might be involved in podocytes to endothelial cells communication in lupus nephritis.