rpS6 Phosphorylation-Mediated Renal Hypertrophy Promotes AKI in Diabetes

Background: Diabetic patients are more susceptible to acute kidney injury (AKI) and have a significantly worse prognosis compared with non-diabetic AKI patients. The mechanisms underlying this increased susceptibility and severity remain poorly understood. Renal hypertrophy is an early and prominent structural alteration in diabetes. Of particular significance is the hypertrophy observed in the renal proximal tubule, which exhibits the most prominent hypertrophy in diabetes and is the major site of damage in AKI. Here we report the effect of genetic deletion of ribosomal protein S6 (rpS6) phosphorylation on AKI in diabetes. Methods: Diabetes was induced in non-phosphorylatable rpS6 knock-in mice (rpS6P–/–) and wild-type littermates (rpS6P+/+) by multiple low-dose streptozotocin (STZ) injections (50 mg/kg/day by daily i.p. for 5 days). After 4 weeks of sustained hyperglycemia, both diabetic and non-diabetic mice were subjected to 18 minutes of bilateral renal ischemia followed by reperfusion (BIR). We assessed renal hypertrophy, ischemic injury, and activation of the mTOR-S6K1-rpS6 signaling axis. Results: Both genotypes developed equivalent hyperglycemia following STZ injections. However, diabetic rpS6P–/– mice exhibited ~50% attenuation of renal hypertrophy compared to diabetic rpS6P+/+ mice. Renal ischemia-reperfusion (IR) is a clinically relevant common cause of AKI. Following bilateral IR (BIR), diabetic rpS6P+/+ mice exhibited elevated TUNEL-positive cells, severe tubular necrosis, and epithelial sloughing, progressing to marked increases in BUN and serum creatinine by 24 hours. In contrast, equally diabetic rpS6P–/– mice showed minimal tubular injury, with significantly lower injury scores, reduced TUNEL positivity, and preserved kidney function. Despite similar phosphorylation of S6K1 (Thr389) between genotypes (indicating a similar level of mTOR activation), diabetic rpS6P+/+ kidneys showed robust rpS6 phosphorylation, which was absent in rpS6P–/– mice. These findings indicate that rpS6 phosphorylation contributes to renal hypertrophy and AKI vulnerability in diabetes. Conclusion: This study provides the first unequivocal evidence that rpS6 phosphorylation–mediated renal hypertrophy underlies the increased susceptibility and severity of AKI in diabetes. Targeting rpS6 phosphorylation may represent a novel strategy for the prevention and treatment of AKI in diabetes. Funding: NIDDK Support