Nestin protects podocyte from injury in lupus nephritis by mitophagy and oxidative stress.
Adult
Animals
Female
Humans
Kidney
/ metabolism
Lupus Nephritis
/ drug therapy
Male
Membrane Proteins
/ metabolism
Mesenchymal Stem Cells
/ drug effects
Mice
Middle Aged
Nestin
/ metabolism
Oxidative Stress
/ drug effects
Podocytes
/ metabolism
Protective Agents
/ metabolism
Proteinuria
/ metabolism
Journal
Cell death & disease
ISSN: 2041-4889
Titre abrégé: Cell Death Dis
Pays: England
ID NLM: 101524092
Informations de publication
Date de publication:
05 05 2020
05 05 2020
Historique:
received:
22
10
2019
accepted:
23
04
2020
revised:
23
04
2020
entrez:
7
5
2020
pubmed:
7
5
2020
medline:
10
4
2021
Statut:
epublish
Résumé
Podocyte injury is the main cause of proteinuria in lupus nephritis (LN). Nestin, an important cytoskeleton protein, is expressed stably in podocytes and is associated with podocyte injury. However, the role of nestin in the pathogenesis of proteinuria in LN remains unclear. The correlations among nestin, nephrin and proteinuria were analyzed in LN patients and MRL/lpr lupus-prone mice. The expression of nestin in mouse podocyte lines (MPCs) and MRL/lpr mice was knocked down to determine the role of nestin in podocyte injury. Inhibitors and RNAi method were used to explore the role of mitophagy and oxidative stress in nestin protection of podocyte from damage. There was a significantly negative correlation between nestin and proteinuria both in LN patients and MRL/lpr mice, whereas the expression of nephrin was positively correlated with nestin. Knockdown of nestin resulted in not only the decrease of nephrin, p-nephrin (Y1217) and mitophagy-associated proteins in cultured podocytes and the podocytes of MRL/lpr mice, but also mitochondrial dysfunction in podocytes stimulated with LN plasma. The expression and phosphorylation of nephrin was significantly decreased by reducing the level of mitophagy or production of reactive oxygen species (ROS) in cultured podocytes. Our findings suggested that nestin regulated the expression of nephrin through mitophagy and oxidative stress to protect the podocytes from injury in LN.
Identifiants
pubmed: 32371936
doi: 10.1038/s41419-020-2547-4
pii: 10.1038/s41419-020-2547-4
pmc: PMC7200703
doi:
Substances chimiques
Membrane Proteins
0
Nestin
0
Protective Agents
0
nephrin
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
319Références
Doria, A., Gatto, M., Zen, M., Iaccarino, L. & Punzi, L. Optimizing outcome in SLE: treating-to-target and definition of treatment goals. Autoimmun. Rev. 13, 770–777 (2014).
doi: 10.1016/j.autrev.2014.01.055
Hajji, M. et al. Factors associated with relapse of lupus nephritis: a single center study of 249 cases. Saudi J. Kidney Dis. Transpl. 28, 1349–1355 (2017).
doi: 10.4103/1319-2442.220863
Ayoub, I., Birmingham, D., Rovin, B. & Hebert, L. Commentary on the current guidelines for the diagnosis of lupus nephritis flare. Curr. Rheumatol. Rep. 21, 12 (2019).
doi: 10.1007/s11926-019-0809-x
Nagase, M. et al. Enhanced aldosterone signaling in the early nephropathy of rats with metabolic syndrome: possible contribution of fat-derived factors. J. Am. Soc. Nephrol. 17, 3438–3446 (2006).
doi: 10.1681/ASN.2006080944
Matsui, I. et al. Active vitamin D and its analogue, 22-oxacalcitriol, ameliorate puromycin aminonucleoside-induced nephrosis in rats. Nephrol. Dial. Transpl. 24, 2354–2361 (2009).
doi: 10.1093/ndt/gfp117
Tomioka, M. et al. Nestin is a novel marker for renal tubulointerstitial injury in immunoglobulin a nephropathy. Nephrology 15, 568–574 (2010).
doi: 10.1111/j.1440-1797.2010.01342.x
Filipovic, N. et al. Immunohistochemical and electronmicroscopic features of mesenchymal-to-epithelial transition in human developing, postnatal and nephrotic podocytes. Histochem. Cell Biol. 147, 481–495 (2017).
doi: 10.1007/s00418-016-1507-7
Chen, J. et al. Differential expression of the intermediate filament protein nestin during renal development and its localization in adult podocytes. J. Am. Soc. Nephrol. 17, 1283–1291 (2006).
doi: 10.1681/ASN.2005101032
Sun, Y. et al. The expression and significance of neuronal iconic proteins in podocytes. PLoS ONE 9, e93999 (2014).
doi: 10.1371/journal.pone.0093999
Eladl, M. A., Elsaed, M., Atef, W., El-Sherbiny, H. & Ultrastructural, M. changes and nestin expression accompanying compensatory renal growth after unilateral nephrectomy in adult rats. Int. J. Nephrol. Renovasc. Dis. 10, 61–76 (2017).
doi: 10.2147/IJNRD.S121473
Liu, W. et al. Nestin protects mouse podocytes against high glucose-induced apoptosis by a cdk5-dependent mechanism. J. Cell Biochem. 113, 3186–3196 (2012).
doi: 10.1002/jcb.24195
Hauser, P. V., Collino, F., Bussolati, B. & Camussi, G. Nephrin and endothelial injury. Curr. Opin. Nephrol. Hypertens. 18, 3–8 (2009).
doi: 10.1097/MNH.0b013e32831a4713
Aoudjit, L. et al. Podocyte protein, nephrin, is a substrate of protein tyrosine phosphatase 1b. J. Signal Transduct. 2011, 376543 (2011).
doi: 10.1155/2011/376543
Xiong, B., Li, M., Xiang, S. & Han, L. A1AR-mediated renal protection against ischemia/reperfusion injury is dependent on HSP27 induction. Int. Urol. Nephrol. 50, 1355–1363 (2018).
doi: 10.1007/s11255-018-1797-x
Liu, J. et al. Knockdown of TRIM27 expression suppresses the dysfunction of mesangial cells in lupus nephritis by FoxO1 pathway. J. Cell Physiol. 234, 11555–11566 (2019).
doi: 10.1002/jcp.27810
Qi, Y. et al. Increased autophagy is cytoprotective against podocyte injury induced by antibody and interferon-α in lupus nephritis. Ann. Rheum. Dis. 77, 1799–1809 (2018).
doi: 10.1136/annrheumdis-2018-213028
Yuan, K. et al. Autophagy plays an essential role in the clearance of pseudomonas aeruginosa by alveolar macrophages. J. Cell Sci. 125, 507–515 (2012).
doi: 10.1242/jcs.094573
Koo, H. S., Kim, S. & Chin, H. J. Remission of proteinuria indicates good prognosis in patients with diffuse proliferative lupus nephritis. Lupus 25, 3–11 (2016).
doi: 10.1177/0961203315595130
Touma, Z., Urowitz, M. B., Ibañez, D. & Gladman, D. D. Time to recovery from proteinuria in patients with lupus nephritis receiving standard treatment. J. Rheumatol. 41, 688–697 (2014).
doi: 10.3899/jrheum.130005
Shankland, S. J. The podocyte’s response to injury: role in proteinuria and glomerulosclerosis. Kidney Int. 69, 2131–2147 (2006).
doi: 10.1038/sj.ki.5000410
Zou, J. et al. Upregulation of nestin, vimentin, and desmin in rat podocytes in response to injury. Virchows Arch. 448, 485–492 (2006).
doi: 10.1007/s00428-005-0134-9
Mathieson, P. W. The podocyte as a target for therapies—new and old. Nat. Rev. Nephrol. 8, 52–56 (2011).
doi: 10.1038/nrneph.2011.171
Fu, R. et al. Podocyte activation of NLRP3 inflammasomes contributes to the development of proteinuria in lupus nephritis. Arthritis Rheumatol. 69, 1636–1646 (2017).
doi: 10.1002/art.40155
Sun, L. et al. A20 overexpression exerts protective effects on podocyte injury in lupus nephritis by downregulating UCH-L1. J. Cell Physiol. 243, 16191–16204 (2019).
doi: 10.1002/jcp.28282
Endlich, K., Kriz, W. & Witzgall, R. Update in podocyte biology. Curr. Opin. Nephrol. Hypertens. 10, 331–340 (2001).
doi: 10.1097/00041552-200105000-00006
Su, W. et al. Expression of nestin in the podocytes of normal and diseased human kidneys. Am. J. Physiol. Regul. Integr. Comp. Physiol. 292, R1761–R1767 (2007).
doi: 10.1152/ajpregu.00319.2006
Elsherbiny, N. M., El-Sherbiny, M. & Said, E. Amelioration of experimentally induced diabetic nephropathy and renal damage by nilotinib. J. Physiol. Biochem. 71, 635–648 (2015).
doi: 10.1007/s13105-015-0428-6
Takagi, H. et al. USP40 gene knockdown disrupts glomerular permeability in zebrafish. Am. J. Physiol. Ren. Physiol. 312, F702–F715 (2017).
doi: 10.1152/ajprenal.00197.2016
Forbes, J. M. et al. Modulation of nephrin in the diabetic kidney: association with systemic hypertension and increasing albuminuria. J. Hypertens. 20, 985–992 (2002).
doi: 10.1097/00004872-200205000-00034
Wang, S. et al. Autophagy-related gene atg5 is essential for astrocyte differentiation in the developing mouse cortex. Embo. Rep. 15, 1053–1061 (2014).
doi: 10.15252/embr.201338343
Xiao, T. et al. Rapamycin promotes podocyte autophagy and ameliorates renal injury in diabetic mice. Mol. Cell Biochem. 394, 145–154 (2014).
doi: 10.1007/s11010-014-2090-7
Jin, J. et al. The novel involvement of podocyte autophagic activity in the pathogenesis of lupus nephritis. Histol. Histopathol. 33, 803–814 (2018).
pubmed: 29446059
Wang, J. et al. Nestin regulates proliferation and invasion of gastrointestinal stromal tumor cells by altering mitochondrial dynamics. Oncogene 35, 3139–3150 (2016).
doi: 10.1038/onc.2015.370
Li, W. et al. FoxO1 promotes mitophagy in the podocytes of diabetic male mice via the PINK1/Parkin pathway. Endocrinology 158, 2155–2167 (2017).
doi: 10.1210/en.2016-1970
Matic, I., Strobbe, D., Di, G. F. & Campanella, M. Molecular biology digest of cell mitophagy. Int. Rev. Cell Mol. Biol. 332, 233–258 (2017).
doi: 10.1016/bs.ircmb.2016.12.003
Al-Waili, N., Al-Waili, H., Al-Waili, T. & Salom, K. Natural antioxidants in the treatment and prevention of diabetic nephropathy; a potential approach that warrants clinical trials. Redox Rep. 22, 99–118 (2017).
doi: 10.1080/13510002.2017.1297885