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Kidney Week

Abstract: PO0925

Altered Protein Translation in the Kidney Precedes the Development of Diabetic Kidney Disease

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

  • Sutton, Timothy A., Indiana University School of Medicine, Division of Nephrology, Indianapolis, Indiana, United States
  • Maier, Bernhard, Indiana University School of Medicine, Division of Nephrology, Indianapolis, Indiana, United States
  • Hato, Takashi, Indiana University School of Medicine, Division of Nephrology, Indianapolis, Indiana, United States
  • Dagher, Pierre C., Indiana University School of Medicine, Division of Nephrology, Indianapolis, Indiana, United States
Background

Diabetic kidney disease (DKD) is one of the most serious complications of diabetes. Diabetes is characterized by a variety of physiologic derangements and maladaptive pathways that contribute to cell stress and the development of DKD. There is mounting evidence in a variety of disease models demonstrating that altered protein translation, a fundamental step in gene expression, is important in both responding and contributing to cell stress. The hypothesis of this study is that altered protein translation precedes the development of overt DKD. It was the aim of this study to undertake a detailed examination of protein translation in the kidney early in the course of diabetes.

Methods

Ribosome footprint profiling (Ribo-seq) was employed to unbiasedly examine translational processes in the kidney at nucleotide level resolution across the whole genome during the develpment of diabetes in db/db mice. RNA-seq was done in parallel to examine transcriptional pathways of translation and augment findings from the translatome.

Results

Ribo-seq in 12 week-old db/db mice and age-matched, background C57BL/6J control mice (BC) demonstrated a marked (50%) global increase in translation in kidneys from db/db mice as compared to BC mice. This findings of increased translation was further supported by polyribosomal profiling and pathway analysis of RNA-seq done in parallel. Increase of global translation was also observed as the vintage of diabetes increased from 9 weeks to 12 weeks in db/db mice. Increased translation in the kidney of important pathgenic mediators were observed in pathways that contribute to alterations in cell cycling (p21), fibrogenesis (fibronectin), inflammation (osteopontin), glucose transport (SGLT2), and oxidative stress (NOX4). Although overall transcription and translation of p53 was not observed early in diabetes, translation of ΔNp53 (Δ40p53), a stress-induced, translationally-regulated isoform of p53 important for development of the diabetic phenotype was found to be increased by Ribo-seq. These findings underscore the importance of examining the translatome in the kidney as a missing omics layer in DKD.

Conclusion

Generalized protein translation is increased in the kidney early in the course of DKD. Pharmacological manipulation of translation may represent a novel therapeutic approach to the development and progression of DKD.

Funding

  • NIDDK Support