SP393
PROTEOME REMODELING IN AGING KIDNEY AND THE ROLE OF MITOCHONDRIAL OXIDATIVE STRESS

INTRODUCTION: Aging is a major risk factor for chronic kidney disease. Free radical theory of aging postulates that reactive oxygen species (ROS) and oxidative damage are major determinants of longevity and mediate aging of several organ systems. However, the direct roles of hydrogen peroxide in kidney aging have not been fully investigated.

METHODS: We examine kidney pathologies and biochemistry of mice overexpressing Glutathione Peroxidase-1 (GPX-1) and wild-type littermates in aging mouse cohort. Laser capture microdissection of the glomeruli followed by unbiased shotgun proteomics analysis was performed. A separate targeted proteomics for metabolic, mitochondrial, proteostasis, antioxidant and peroxisomal pathways was performed for kidney tubules.

RESULTS: We demonstrated that kidney aging in mice closely recapitulate the pathologies of human kidney aging, including age-dependent glomerulosclerosis, tubular atrophy, interstitial fibrosis resulting in loss of cortical mass. Scavenging ROS by low dose transgenic overexpression of glutathione peroxidase-1 (GPX-1 Tg) ameliorated kidney aging pathologies, concomitant with better protection from age-related protein and lipid oxidative damage. Using laser capture microdissection followed by label-free shotgun proteomics analysis, we demonstrate that glomerular proteome aging is characterized by the decline in several heat shock proteins and critical cytoskeletal proteins essential to maintain normal function of glomerular filtration as well as increased accumulation of apolipoprotein E and other inflammatory molecules. GPX-1 Tg partially attenuate the age-related glomerular proteome remodeling. Targeted proteomics analysis of metabolic proteins in kidney tubules suggests an age-related decreased in fatty acid oxidation and increased in glycolytic enzymes, decreased in antioxidant defense and increased in molecular chaperones. Furthermore, kidney aging is associated with significant decline in tissue klotho, which is not protected by GPX-1 Tg, suggesting that ROS is downstream of age-dependent decline in klotho.

CONCLUSIONS: In summary, our current study provides a direct evidence of the critical roles of hydrogen peroxide in aging kidney pathologies and age-related glomerular and tubular proteome remodeling.