| First Author | Chuang PY | Year | 2017 |
| Journal | Am J Physiol Renal Physiol | Volume | 313 |
| Issue | 3 | Pages | F621-F628 |
| PubMed ID | 28615249 | Mgi Jnum | J:281987 |
| Mgi Id | MGI:6381302 | Doi | 10.1152/ajprenal.00255.2017 |
| Citation | Chuang PY, et al. (2017) Reduction in podocyte SIRT1 accelerates kidney injury in aging mice. Am J Physiol Renal Physiol 313(3):F621-F628 |
| abstractText | 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 cell 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(RNAi)) and control mice that express shRNA for luciferase (Pod-Luci(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(RNAi) mice compared with aged Pod-Luci(RNAi) mice. Although podocyte-specific markers decreased in aged mice compared with the young controls, the decrease was further exacerbated in aged Pod-Sirt1(RNAi) compared with Pod-Luci(RNAi) mice. Interestingly, expression of cellular senescence markers was significantly higher in the glomeruli of Pod-Sirt1(RNAi) mice than Pod-Luci(RNAi) mice, suggesting that cellular senescence may contribute to podocyte loss in aging kidneys. Finally, we confirmed that Pod-Sirt1(RNAi) glomeruli were associated with reduced activation of the transcription factors peroxisome proliferator-activated receptor (PPAR)-alpha coactivador-1 (PGC1alpha)/PPARgamma, forkhead box O (FOXO)3, FOXO4, and p65 NF-kappaB, through SIRT1-mediated deacetylation. Together, our data suggest that SIRT1 may be a potential therapeutic target to treat patients with aging-related kidney disease. |
