Dampening Protein Translation Abrogates the Development of Albuminuria in a Diabetic Mouse Model
- Diabetic Kidney Disease: Basic - II
November 04, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Diabetic Kidney Disease
- 701 Diabetic Kidney Disease: Basic
- Long, Anne, Indiana University School of Medicine, Indianapolis, Indiana, United States
- Zollman, Amy, Indiana University School of Medicine, Indianapolis, Indiana, United States
- Hato, Takashi, Indiana University School of Medicine, Indianapolis, Indiana, United States
- Sutton, Timothy A., Indiana University School of Medicine, Indianapolis, Indiana, United States
- Overstreet, Jessica Marie, Indiana University School of Medicine, Indianapolis, Indiana, United States
- Dagher, Pierre C., Indiana University School of Medicine, Indianapolis, Indiana, United States
Diabetes remains a major cause of chronic kidney disease and end stage kidney disease. The pathophysiologic processes leading to the development of kidney disease in diabetes are poorly understood because it is not common practice to obtain kidney biopsies in diabetic patients without diabetic kidney disease (DKD). We have previously demonstrated that translation, the fundamental process in protein synthesis, is increased in the kidney in a mouse model of diabetes. This increase in translation was observed prior to the onset of DKD. Here we investigate whether direct inhibitors of protein translation, such as tetracyclines, can mitigate the development of proteinuria.
Db/db mice on a Kaliss strain background which are prone to developing manifestations of DKD over time were used. These mice demonstrate an increase in translation starting as early as eight weeks. Treatment with minocycline (50mg/kg daily x 4 weeks by gavage) was started at 8 weeks and the kidneys were harvested for polyribosomal profiling (PRP). In a parallel set of experiments, 6-week old Db/Db mice (n=10) were treated for up to 10 weeks with minocycline (50mg/kg daily in drinking water) and urine was collected weekly for measurement of albuminuria. Finally, a separate group of Db/Db mice were treated with the SGLT2 inhibitor (dapagliflozin; 1mg/kg, po) for 4 weeks and kidneys were harvested for PRP.
Treatment with minocycline resulted in a 30% reduction in global protein translation as measured by PRP. Fifty percent of the vehicle control treated mice developed significant albuminuria (albumin/creatinine ratio between 0.6-6 μg/μg). In contrast, in all mice treated with minocycline allbumin/creatinine ratios < 0.5 μg/μg. Interestingly, SGLT2 inhibition also resulted in reduction of protein translation as measured by PRP.
Increased protein synthesis in the kidney is a feature of diabetes before the onset of DKD. Pharmacologic strategies to reduce protein synthesis may serve as a new therapeutic avenue to prevent the development of DKD.
- NIDDK Support