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Effects of Chronic Intermittent Hypoxia and Subsequent Normoxic Recovery on Renal Senescence and the PI3K/Akt/P21
HaiBo Li1, MingZhi Chen1, Fang Han2
1Department of Endocrinology, The First Affiliated Hospital, Baotou Medical College, Inner Mongolia University of Science and Technology, Baotou, Inner Mongolia, People's Republic of China.
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.
