Increased cellular senescence in the murine and human stenotic kidney: Effect of mesenchymal stem cells

• Published in: Journal of cellular physiology Vol. 236; no. 2; pp. 1332 - 1344
• Main Authors: Kim, Seo Rin, Zou, Xiangyu, Tang, Hui, Puranik, Amrutesh S., Abumoawad, Abdelrhman M., Zhu, Xiang‐Yang, Hickson, LaTonya J., Tchkonia, Tamara, Textor, Stephen C., Kirkland, James L., Lerman, Lilach O.
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01.02.2021
• Subjects: Adipose tissue; Adipose Tissue - cytology; Animals; Autografts; beta-Galactosidase - genetics; cellular senescence; Cellular Senescence - genetics; Cellular stress response; Cyclin-dependent kinase inhibitor p21; Density; Disease Models, Animal; Exosomes; Exosomes - genetics; Fibrosis; Gene expression; Humans; Hypertension; Inflammation - genetics; Inflammation - pathology; Inflammation - therapy; Injuries; Ischemia; kidney; Kidney - metabolism; Kidney - pathology; Kidneys; Mesenchymal Stem Cell Transplantation; Mesenchymal stem cells; Mesenchymal Stem Cells - cytology; Mesenchymal Stem Cells - metabolism; Mice; Phenotypes; Ras protein; Renal artery; renal artery obstruction; Renal Artery Obstruction - genetics; Renal Artery Obstruction - pathology; Renal Artery Obstruction - therapy; Renal function; Senescence; Stem cell transplantation; Stem cells; Stenosis; β-Galactosidase; kidney; cellular senescence; renal artery obstruction; exosomes; mesenchymal stem cells
• ISSN: 0021-9541; 1097-4652
• DOI: 10.1002/jcp.29940

Cell stress may give rise to insuperable growth arrest, which is defined as cellular senescence. Stenotic kidney (STK) ischemia and injury induced by renal artery stenosis (RAS) may be associated with cellular senescence. Mesenchymal stem cells (MSCs) decrease some forms of STK injury, but their ability to reverse senescence in RAS remains unknown. We hypothesized that RAS evokes STK senescence, which would be ameliorated by MSCs. Mice were studied after 4 weeks of RAS, RAS treated with adipose tissue‐derived MSCs 2 weeks earlier, or sham. STK senescence‐associated β‐galactosidase (SA‐β‐Gal) activity was measured. Protein and gene expression was used to assess senescence and the senescence‐associated secretory phenotype (SASP), and staining for renal fibrosis, inflammation, and capillary density. In addition, senescence was assessed as p16+ and p21+ urinary exosomes in patients with renovascular hypertension (RVH) without or 3 months after autologous adipose tissue‐derived MSC delivery, and in healthy volunteers (HV). In RAS mice, STK SA‐β‐Gal activity increased, and senescence and SASP marker expression was markedly elevated. MSCs improved renal function, fibrosis, inflammation, and capillary density, and attenuated SA‐β‐Gal activity, but most senescence and SASP levels remained unchanged. Congruently, in human RVH, p21+ urinary exosomes were elevated compared to HV, and only slightly improved by MSC, whereas p16+ exosomes remained unchanged. Therefore, RAS triggers renal senescence in both mice and human subjects. MSCs decrease renal injury, but only partly mitigate renal senescence. These observations support exploration of targeted senolytic therapy in RAS. Stenotic kidney (STK) ischemia induced by renal artery stenosis (RAS) is associated with cellular senescence in mice and human subjects. Mesenchymal stem cell (MSC) treatment decreases some forms of STK injury, but only partly mitigates renal senescence.