Reduction in podocyte SIRT1 accelerates kidney injury in aging mice

Autor: Weijing Cai, Xuezhu Li, Rabi Yacoub, Lu Fang, Kyung Lee, John Cijiang He, Peter Y. Chuang, Jin Xu
Rok vydání: 2017
Předmět:
0301 basic medicine
Aging
Pathology
Physiology
Cell Cycle Proteins
medicine.disease_cause
Podocyte
Mice
Glomerulonephritis
0302 clinical medicine
Sirtuin 1
RNA
Small Interfering
Cellular Senescence
Podocytes
Incidence (epidemiology)
Forkhead Box Protein O3
Age Factors
Acetylation
Forkhead Transcription Factors
Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
Phenotype
medicine.anatomical_structure
8-Hydroxy-2'-Deoxyguanosine
Gene Knockdown Techniques
RNA Interference
hormones
hormone substitutes
and hormone antagonists
Signal Transduction
Research Article
Senescence
medicine.medical_specialty
Genotype
Cellular senescence
Biology
03 medical and health sciences
Internal medicine
Elderly population
medicine
Kidney injury
Albuminuria
Animals
Renal Insufficiency
Chronic
Transcription Factor RelA
Deoxyguanosine
medicine.disease
Oxidative Stress
030104 developmental biology
Endocrinology
030217 neurology & neurosurgery
Oxidative stress
Kidney disease
Zdroj: American Journal of Physiology-Renal Physiology. 313:F621-F628
ISSN: 1522-1466
1931-857X
Popis: 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-Sirt1RNAi) and control mice that express shRNA for luciferase (Pod-LuciRNAi). 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-Sirt1RNAimice compared with aged Pod-LuciRNAimice. Although podocyte-specific markers decreased in aged mice compared with the young controls, the decrease was further exacerbated in aged Pod-Sirt1RNAicompared with Pod-LuciRNAimice. Interestingly, expression of cellular senescence markers was significantly higher in the glomeruli of Pod-Sirt1RNAimice than Pod-LuciRNAimice, suggesting that cellular senescence may contribute to podocyte loss in aging kidneys. Finally, we confirmed that Pod-Sirt1RNAiglomeruli were associated with reduced activation of the transcription factors peroxisome proliferator-activated receptor (PPAR)-α coactivador-1 (PGC1α)/PPARγ, forkhead box O (FOXO)3, FOXO4, and p65 NF-κB, through SIRT1-mediated deacetylation. Together, our data suggest that SIRT1 may be a potential therapeutic target to treat patients with aging-related kidney disease.
Databáze: OpenAIRE
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