Mechanisms and consequences of oxidant-induced renal preconditioning: an Nrf2-dependent, P21-independent, anti-senescence pathway
| Autor: | Richard A. Zager, Ali C.M. Johnson |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
Cyclin-Dependent Kinase Inhibitor p21
Male 0301 basic medicine Senescence NF-E2-Related Factor 2 030232 urology & nephrology Protoporphyrins Endogeny Mice 03 medical and health sciences 0302 clinical medicine Downregulation and upregulation medicine Animals Ischemic Preconditioning Cellular Senescence Mice Knockout Transplantation Kidney business.industry Cell Cycle Checkpoints Acute Kidney Injury Oxidants Heme oxygenase 030104 developmental biology medicine.anatomical_structure GCLC Gene Expression Regulation Nephrology Heme Oxygenase (Decyclizing) Cancer research Ischemic preconditioning business Cell aging |
| Zdroj: | Nephrology Dialysis Transplantation. 33:1927-1941 |
| ISSN: | 1460-2385 0931-0509 |
| DOI: | 10.1093/ndt/gfy029 |
| Popis: | Background P21, a cyclin kinase inhibitor, is upregulated by renal 'ischemic preconditioning' (IPC), and induces a 'cytoresistant' state. However, P21-induced cell cycle inhibition can also contribute to cellular senescence, a potential adverse renal event. Hence, this study assessed whether: (i) IPC-induced P21 upregulation is associated with subsequent renal senescence; and (ii) preconditioning can be established 'independent' of P21 induction and avoid a post-ischemic senescent state? Methods CD-1 mice were subjected to either IPC (5-15 min) or to a recently proposed 'oxidant-induced preconditioning' (OIP) strategy (tin protoporphyrin-induced heme oxygenase inhibition +/- parental iron administration). P21 induction [messenger RNA (mRNA)/protein], cell proliferation (KI-67, phosphohistone H3 nuclear staining), kidney senescence (P16ink4a; P19Arf mRNAs; senescence-associated beta-galactosidase levels) and resistance to ischemic acute kidney injury were assessed. Results IPC induced dramatic (10-25×) and persistent P21 activation and 'downstream' tubular senescence. Conversely, OIP did not upregulate P21, it increased, rather than decreased, cell proliferation markers, and it avoided a senescence state. OIP markedly suppressed ischemia-induced P21 up-regulation, it inhibited the development of post-ischemic senescence and it conferred near-complete protection against ischemic acute renal failure (ARF). To assess OIP's impact on a non-P21-dependent cytoprotective pathway, its ability to activate Nrf2, the so-called 'master regulator' of endogenous cell defenses, was assessed. Within 4 h, OIP activated each of three canonical Nrf2-regulated genes (NQO1, SRXN1, GCLC; 3- to 5-fold mRNA increases). Conversely, this gene activation pathway was absent in Nrf2-/- mice, confirming Nrf2 specificity. Nrf2-/- mice also did not develop significant OIP-mediated protection against ischemic ARF. Conclusions OIP (i) activates the cytoprotective Nrf2, but not the P21, pathway; (ii) suppresses post-ischemic P21 induction and renal senescence; and (iii) confers marked protection against ischemic ARF. In sum, these findings suggest that OIP may be a clinically feasible approach for safely activating the Nrf2 pathway, and thereby confer protection against clinical renal injury. |
| Databáze: | OpenAIRE |
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