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

Seo Rin Kim, Xiangyu Zou, Hui Tang, Amrutesh S. Puranik, Abdelrhman M. Abumoawad, Xiang Yang Zhu, La Tonya J. Hickson, Tamara Tchkonia, Stephen C. Textor, James L. Kirkland, Lilach O. Lerman

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
JournalJournal of Cellular Physiology
DOIs
StateAccepted/In press - 2020

Keywords

  • cellular senescence
  • exosomes
  • kidney
  • mesenchymal stem cells
  • renal artery obstruction

ASJC Scopus subject areas

  • Physiology
  • Clinical Biochemistry
  • Cell Biology

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