학술논문
Reduction in podocyte SIRT1 accelerates kidney injury in aging mice
Document Type
Author abstract
Report
Report
Author
Source
American Journal of Physiology (Consolidated). Sept, 2017, Vol. 313 Issue 3, pF621, 8 p.
Subject
Language
English
ISSN
0002-9513
Abstract
Both the incidence and prevalence of chronic kidney disease are increasing in the elderly population. Although aging is known to induce kidney injury, the underlying molecular mechanisms remain unclear. Sirtuin 1 (Sirt1), a longevity gene, is known to protect kidney ceil injury from various cellular stresses. In previous studies, we showed that the podocyte-specific loss of Sirt1 aggravates diabetic kidney injury. However, the role of Sirt1 in aging-induced podocyte injury is not known. Therefore, in this study we sought to determine the effects of podocyte-specific reduction of Sirt1 in age-induced kidney injury. We employed the inducible podocyte-specific Sirt1 knockdown mice that express shRNA against Sirt1 (Pod-[Sirt1.sup.RNAi]) and control mice that express shRNA for luciferase (Pod-[Luci.sup.RNAi]). We found that reduction of podocyte Sirt1 led to aggravated aging-induced glomerulosclerosis and albuminuria. In addition, urinary level of 8-hydroxy-2'-deoxyguanosine (8-OHdG), a marker of oxidative stress, was markedly increased in aged Pod-[Sirt1.sup.RNAi] mice compared with aged Pod-[Luci.sup.RNAi] mice. Although podocyte-specific markers decreased in aged mice compared with the young controls, the decrease was further exacerbated in aged Pod-[Sirt1.sup.RNAi] compared with Pod-[Luci.sup.RNAi] mice. Interestingly, expression of cellular senescence markers was significantly higher in the glomeruli of Pod-[Sirt1.sup.RNAi] mice than Pod-[Luci.sup.RNAi] mice, suggesting that cellular senescence may contribute to podocyte loss in aging kidneys. Finally, we confirmed that Pod-[Sirt1.sup.RNAi] glomeruli were associated with reduced activation of the transcription factors peroxisome proliferator-activated receptor (PPAR)-[alpha] coactivador-1 (PGC1[alpha]/PPAR[gamma], forkhead box O (FOXO)3, F0X04, and p65 NF-[kappa]B, through SIRT1-mediated deacetylation. Together, our data suggest that SIRT1 may be a potential therapeutic target to treat patients with aging-related kidney disease. SIRT1; aging; chronic kidney disease; senescence; podocytes doi: 10.1152/ajprenal.00255.2017.