Transition between Healthy Aging and Renal Dysfunction during Natural Aging: Role of p21, p16, Nicotinamide Adenine Dinucleotide Phosphate Hydrogen Oxidase, Nuclear Factor-Kappa B, and Cyclooxygenase-2.

Abstract

Introduction: Aging is a key risk factor for progressive kidney disease, yet the mechanisms underlying age-related renal dysfunction remain poorly understood. This study aimed to investigate the role of cyclooxygenase-2 (COX-2) in the transition from healthy renal aging to dysfunction, focusing on its involvement in cellular senescence, inflammation, and oxidative stress.

Methods: Male Swiss mice aged 3 (young), 12 (middle-aged), and 18 (old) months were analyzed to assess renal function via blood and 24-h urine collection. Protein expression was evaluated by Western blot, and renal collagenase and matrix metalloproteinase 2 (MMP-2) activities were assessed by immunofluorescence. Neutrophil accumulation was measured by myeloperoxidase (MPO) activity, cytokine levels were measured by ELISA, and oxidative stress was assessed by fluorescence.

Results: Old mice showed elevated expression of senescence markers (p53, p21, and p16), COX-2, nuclear factor-kappa B (NF-κB p65), and pro-inflammatory cytokines (IL-6, MCP-1), along with increased MPO activity. Collagenase and MMP-2 activities were also enhanced, particularly in glomerular and tubular regions. Furthermore, upregulation of NADPH oxidase subunits and decreased antioxidant enzyme expression resulted in heightened renal ROS production. These molecular changes were accompanied by significant renal dysfunction, as indicated by reduced creatinine clearance and increased albumin-to-creatinine ratio (ACR). Notably, COX-2 expression positively correlated with inflammation, oxidative stress, and renal dysfunction. In contrast, middle-aged mice exhibited early signs of senescence and oxidative stress without overt inflammation or functional impairment.

Conclusion: These findings highlight a critical transitional phase in kidney aging, where early senescence and oxidative stress emerge before functional decline. COX-2 may serve as a central mediator in this process, offering a potential therapeutic target for mitigating age-related renal dysfunction.