Tubular Hypertrophy and AKI Susceptibility in Diabetes - PROJECT SUMMARY Despite advances in treatment, acute kidney injury (AKI) patients requiring dialysis still face a high mortality rate of 50-60%, and survivors have a 28-fold increased risk of progressing to chronic kidney disease (CKD), leading to end-stage renal disease (ESRD). Diabetic patients are particularly susceptible to AKI and suffer worse prognoses compared to non-diabetic patients. However, the underlying mechanisms remain unclear. Renal hypertrophy, an early alteration in both type 1 and type 2 diabetes, particularly affects proximal tubules, which are also primary sites of AKI damage. We and others previously demonstrated that activation of the mTORC1-S6K1-rpS6 pathway drives diabetic renal hypertrophy through increased protein synthesis. We reported that S6K1 knockout mice exhibited ~70% inhibition of renal hypertrophy induced by either uninephrectomy or diabetes. The goal of this project is to investigate the molecular changes underlying diabetic renal hypertrophy and its impact on AKI susceptibility and severity in diabetes. Preliminary studies revealed that genetic deletion of ribosomal protein S6 phosphorylation sites (rpS6P–/–) inhibited ~50% of diabetes-induced renal hypertrophy and significantly reduced AKI severity. We also found that autophagy, a cellular degradation pathway, is impaired in diabetic proximal tubules. Our preliminary data further revealed that endoplasmic reticulum (ER) stress is heightened, activating the PERK pathway, in diabetic kidneys in response to ischemic AKI. Based on these observations, our central hypothesis is that, in addition to mTORC1/S6K1/rpS6P-mediated protein synthesis, the impairment of autophagic protein degradation contributes to diabetic tubular hypertrophy. Thus, in hypertrophic tubular cells, excessive protein accumulation and protein aggregate formation result in an elevated basal level of ER stress. Consequently, even a mild additional ER stress-inducing insult (e.g., a brief ischemia- reperfusion insult) may trigger aberrant activation of the PERK pathway, leading to ER stress-induced cell death and exacerbated AKI. We believe this is a major mechanism that underlies the increased AKI susceptibility and severity in diabetes. To test this hypothesis, we will: (1) determine the contribution of impaired autophagy to tubular hypertrophy in diabetes, (2) investigate the impact of tubular hypertrophy on AKI susceptibility in diabetes, (3) define the role of autophagy impairment in AKI susceptibility of diabetic kidneys, and (4) elucidate the role of heightened ER stress and PERK signaling in AKI severity in diabetes. Combining expertise in renal hypertrophy and AKI research, this project will advance the understanding of renal hypertrophy and AKI susceptibility in diabetes. By elucidating the roles of renal hypertrophy, impaired autophagy, and ER stress leading to aberrant PERK activation, this project will lead to the identification of novel therapeutic targets for preventing and/or treating AKI in diabetic patients, ultimately improving clinical outcomes and reducing mortality rates.
