Progressive Cellular Senescence Mediates Renal Dysfunction in Ischemic Nephropathy
| Autor: | Alireza Khodadadi-Jamayran, Stephen C. Textor, Timothy B. Niewold, Xiangyang Zhu, Ian Taylor, Amir Lerman, Tamara Tchkonia, Lilach O. Lerman, Xiao Jun Chen, James L. Kirkland, Amrutesh S. Puranik, Seo Rin Kim, La Tonya J. Hickson, Bennett G. Childs, Kai Jiang |
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| Rok vydání: | 2021 |
| Předmět: |
Male
0301 basic medicine Dasatinib Gene Expression Apoptosis Kidney Renal artery stenosis Mice 0302 clinical medicine Ischemia CDKN2A Cellular Senescence Caspase 8 General Medicine Up-Regulation Nephrology 030220 oncology & carcinogenesis Single-Cell Analysis Heparin-binding EGF-like Growth Factor Cyclin-Dependent Kinase Inhibitor p21 Senescence Epithelial-Mesenchymal Transition Mice Transgenic Renal Artery Obstruction Tacrolimus 03 medical and health sciences Downregulation and upregulation medicine Animals Humans Cyclin-Dependent Kinase Inhibitor p19 Renal Insufficiency Chronic Senolytic Protein Kinase Inhibitors Cyclin-Dependent Kinase Inhibitor p16 Renal ischemia Sequence Analysis RNA business.industry Mesenchymal stem cell Epithelial Cells medicine.disease Enzyme Activation Mice Inbred C57BL Disease Models Animal Basic Research 030104 developmental biology p21-Activated Kinases Chronic Disease Cancer research Osteopontin business |
| Zdroj: | J Am Soc Nephrol |
| ISSN: | 1533-3450 1046-6673 |
| Popis: | BACKGROUND: Peripheral vascular diseases may induce chronic ischemia and cellular injury distal to the arterial obstruction. Cellular senescence involves proliferation arrest in response to stress, which can damage neighboring cells. Renal artery stenosis (RAS) induces stenotic-kidney dysfunction and injury, but whether these arise from cellular senescenceand their temporal pattern remain unknown. METHODS: Chronic renal ischemia was induced in transgenic INK-ATTAC and wild type C57BL/6 mice by unilateral RAS, and kidney function (in vivo micro-MRI) and tissue damage were assessed. Mouse healthy and stenotic kidneys were analyzed using unbiased single-cell RNA-sequencing. To demonstrate translational relevance, cellular senescence was studied in human stenotic kidneys. RESULTS: Using intraperitoneal AP20187 injections starting 1, 2, or 4 weeks after RAS, selective clearance of cells highly expressing p16(Ink4a) attenuated cellular senescence and improved stenotic-kidney function; however, starting treatment immediately after RAS induction was unsuccessful. Broader clearance of senescent cells, using the oral senolytic combination dasatinib and quercetin, in C57BL/6 RAS mice was more effective in clearing cells positive for p21 (Cdkn1a) and alleviating renal dysfunction and damage. Unbiased, single-cell RNA sequencing in freshly dissociated cells from healthy and stenotic mouse kidneys identified stenotic-kidney epithelial cells undergoing both mesenchymal transition and senescence. As in mice, injured human stenotic kidneys exhibited cellular senescence, suggesting this process is conserved. CONCLUSIONS: Maladaptive tubular cell senescence, involving upregulated p16 (Cdkn2a), p19 (Cdkn2d), and p21 (Cdkn1a) expression, is associated with renal dysfunction and injury in chronic ischemia. These findings support development of senolytic strategies to delay chronic ischemic renal injury. |
| Databáze: | OpenAIRE |
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