Abstract: SA-PO0261
Inhibition of S6K1-Mediated Renal Hypertrophy Protects Against AKI in Diabetes
Session Information
- AKI: Mechanisms - Cell Signaling
October 24, 2026 | Location: Exhibit Hall A, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Acute Kidney Injury
- 103 AKI: Mechanisms
Authors
- Yuan, Jialing, Augusta University, Augusta, Georgia, United States
- Dai, Caihong, Augusta University, Augusta, Georgia, United States
- Chen, Jian-Kang, Augusta University, Augusta, Georgia, United States
Background
Diabetes markedly increases susceptibility to acute kidney injury (AKI) and worsens clinical outcomes; however, the underlying mechanisms remain poorly understood. Renal hypertrophy (RH) is the earliest structural alteration in diabetic kidneys, with proximal tubules exhibiting the most prominent hypertrophy. Proximal tubules are also the primary site of injury in AKI. Here, we tested the hypothesis that S6 kinase 1 (S6K1)-mediated RH is a critical mechanism driving the increased susceptibility and severity of AKI in diabetes.
Methods
Diabetes was induced in ribosomal protein S6 phosphorylation-deficient knock-in (rpS6P−/−) mice, S6K1 knockout (S6K1−/−) mice, and their wild-type littermates by low-dose streptozotocin (STZ) injections (50 mg/kg/day, i.p. for 5 days). After 4 weeks of sustained hyperglycemia, mice underwent bilateral renal ischemia-reperfusion (BIR). Pharmacologic S6K1 inhibition was also evaluated. S6K1-rpS6 signaling, renal hypertrophy, kidney injury scores, renal function, and survival were assessed.
Results
STZ induced comparable hyperglycemia in all genotypes. In wild-type diabetic mice, a mild ischemic insult (18-min BIR) caused significant AKI characterized by tubular necrosis, epithelial cell sloughing, intratubular cast formation, increased kidney injury scores, and elevated BUN and serum creatinine, whereas non-diabetic wild-type mice were largely protected. A moderate insult (22-min BIR) induced AKI in both diabetic and non-diabetic mice, but injury was significantly more severe in diabetic hypertrophied kidneys. A severe insult (25-min BIR) resulted in substantially greater mortality in diabetic mice within 7 days after BIR. Genetic inhibition of rpS6 phosphorylation reduced diabetes-induced RH by ~50% and significantly attenuated AKI. S6K1 deficiency inhibited RH by ~70% and provided greater protection against AKI, supporting a dose-dependent relationship between suppression of renal hypertrophy and renoprotection. Pharmacologic S6K1 inhibition similarly reduced RH and significantly protected against AKI.
Conclusion
This study provides genetic and pharmacological evidence that attenuation of S6K1-dependent diabetic renal hypertrophy is sufficient to markedly attenuate AKI susceptibility and severity. These findings identify the S6K1-rpS6 signaling pathway and associated renal hypertrophy as promising therapeutic targets for preventing ischemic AKI in high-risk diabetic patients.
Funding
- NIDDK Support