Effects of Chronic Intermittent Hypoxia and Subsequent Normoxic Recovery on Renal Senescence and the PI3K/Akt/P21 Pathway in Rats.

Abstract

Background: CIH, the hallmark of OSA, is a recognized driver of multi-organ injury. While its contribution to renal dysfunction is acknowledged, the specific roles of key senescence-regulating pathways-particularly the PI3K/Akt/p21 axis and the anti-aging protein Klotho-in CIH-induced renal senescence remain largely unexplored.

Purpose: This study aimed to investigate the effects of CIH and subsequent normoxic reoxygenation on renal senescence in rats, and to elucidate the dynamic involvement of the PI3K/Akt/p21 pathway and the anti-aging protein Klotho in this process.

Methods: Forty 5-week-old male Sprague-Dawley rats were randomly assigned to NC and CIH groups. The CIH group was exposed to IH (range 6.5-7.5%, 30 cycles/h, 8 h/day) for 8 weeks, followed by a 4-week normoxic recovery period. Renal function (SCr, BUN,CysC), histopathology (cortex-to-medulla ratio, tubular epithelial density), and the expression of senescence-related molecules (p21, Klotho, PI3K/AKT pathway components) were assessed at weeks 0, 8, and 12. Statistical significance was determined by two-way ANOVA with Tukey's post hoc test.

Results: Following 8 weeks of CIH exposure, rats exhibited significant renal dysfunction, with SCr increased by 21.3%, BUN by 24.0%, and CysC by 27.9% compared to controls (all P<0.05), alongside histopathological alterations including cortical atrophy, medullary expansion, and reduced tubular epithelial density (P<0.05).These changes were associated with upregulation of p21 and downregulation of PI3K/AKT signaling and Klotho (P<0.05). After 4 weeks of normoxic recovery, renal function and PI3K/Akt/p21 signaling were largely restored (P>0.05 vs NC). However, cortical-medullary structural imbalance and suppressed Klotho expression persisted (P<0.05). Statistical significance was determined by two-way ANOVA with Tukey's post hoc test).

Conclusion: CIH induces a partially reversible renal senescence phenotype in rats, which is associated with dynamic modulation of the PI3K/Akt/p21 axis. The persistent suppression of Klotho may underlie irreversible structural injury, providing novel mechanistic insights into OSA-associated kidney disease.