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. 2022 Aug 30;61(9):3830-3840.
doi: 10.1093/rheumatology/keac037.

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

Zhaomin Mao  1   2 , Ying Tan  1 , Juan Tao  1 , Linlin Li  1 , Hui Wang  3 , Feng Yu  1   4 , Andras Perl  5 , Minghui Zhao  1   2
Affiliations

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

Zhaomin Mao et al. Rheumatology (Oxford). .

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.

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Figures

Fig. 1
Fig. 1
Immunohistochemistry staining for mTOR activation in the glomeruli and tubulointerstitial area of renal specimens (A, B) Immunohistochemical staining of p-RPS6 (Ser235/236) (A) and p-AKT (Ser473) (B) in the glomeruli (above) and tubulointerstitium (below) of LN patients, DN patients, MCD patients and NCs. (C, D) The mean optical density of p-RPS6 (Ser235/236) (C) and p-AKT (Ser473) (D) in the glomeruli. (E, F) The mean optical density of p-RPS6 (Ser235/236) in the glomeruli (E) and tubulointerstitium (F) of different subclasses. (G, H) The mean optical density of p-AKT (Ser473) in the glomeruli (G) and tubulointerstitium (H). (I, J) The mean optical density of p-AKT (Ser473) in the glomeruli (I) and tubulointerstitium (J) of different subclasses. mTOR: mammalian target of rapamycin; DN: diabetic nephropathy; MCD: minimal change disease; NCs: normal controls.
Fig. 2
Fig. 2
The association of mTOR activation with renal pathologic indices in LN patients (A) The association between mTORC1 and mTORC2 activation in glomeruli and tubulointerstitium, and the total AI and CI. (B–D) mTORC1 activation in glomeruli with pathologic indices, including endocapillary hypercellularity (B), neutrophils/karyorrhexis (C) and cellular-fibrocellular crescents (D). (E–G) mTORC1 activation in the tubulointerstitium with pathological indices, including interstitial inflammation (E), tubular atrophy (F) and interstitial fibrosis (G). mTOR: mammalian target of rapamycin; AI: activity indices; CI: chronicity indices.
Fig. 3
Fig. 3
Kaplan–Meier analysis of composite endpoints between the high and low mTORC1 activation groups (A, B) Kaplan–Meier analysis of composite endpoints between the high and low mTORC1 activation groups in glomeruli (A) and tubulointerstitium (B) (dichotomy based on the mean optical density of mTORC1 activation). (C) Kaplan–Meier analysis of composite endpoints between the group with high mTORC1 pathway activation (both in glomeruli and tubulointerstitium) and low mTORC1 activation. (D, E) Kaplan–Meier analysis of composite endpoints between the different mTORC1 activation groups in the glomeruli (D) and tubulointerstitium (E) (quartering based on the mean optical density of mTORC1 activation). mTOR: mammalian target of rapamycin.
Fig. 4
Fig. 4
Bioinformatic analysis of the high and low renal mTORC1 activation groups in the kidney of LN patients The samples were stratified according to mTORC1 activation as high mTORC1 activation and low mTORC1 activation groups. (A) The enriched pathways identified by GSEA. (B) GSEA of mTORC1 signalling pathway between the high and low mTORC1 activation groups. (C) The volcano plot of differentially expressed proteins based on the threshold (fold-change ≥ 1.5, P < 0.05). (D, E) KEGG (D) and GO biological process analysis (E) were performed among the upregulated proteins [fold-change (high/low mTORC1 activation) ≥ 1.5, P < 0.05]. (F, G) KEGG (F) and GO biological process analysis (G) were performed among the downregulated proteins [fold-change (low/high mTORC1 activation) < 1.5, P < 0.05]. mTOR: mammalian target of rapamycin; GSEA: gene set enrichment analysis; KEGG; Kyoto Encyclopedia of Genes and Genomes; GO: Gene Ontology.
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References

    1. Yu F, Haas M, Glassock R, Zhao MH.. Redefining lupus nephritis: clinical implications of pathophysiologic subtypes. Nat Rev Nephrol 2017;13:483–95. - PubMed
    1. Cameron JS. Lupus nephritis. J Am Soc Nephrol 1999;10:413–24. - PubMed
    1. D’Cruz DP, Khamashta MA, Hughes GR.. Systemic lupus erythematosus. Lancet 2007;369:587–96. - PubMed
    1. Ginzler EM, Dooley MA, Aranow C. et al. Mycophenolate mofetil or intravenous cyclophosphamide for lupus nephritis. N Engl J Med 2005;353:2219–28. - PubMed
    1. Anders HJ, Saxena R, Zhao MH. et al. Lupus nephritis. Nat Rev Dis Primers 2020;6:7. - PubMed

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