Abstract: SA-PO511
Cell Proliferation of Proximal Tubular Epithelia Leads to Renal Hypertrophy in Early Diabetic Nephropathy
Session Information
- Diabetic Kidney Disease: Basic - III
November 09, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Diabetic Kidney Disease
- 601 Diabetic Kidney Disease: Basic
Authors
- Uehara, Noriko, Kyoto Prefectural University of Medicine, Kyoto, Japan
- Kusaba, Tetsuro, Kyoto Prefectural University of Medicine, Kyoto, Japan
- Tomita, Aya, Kyoto Prefectural University of Medicine, Kyoto, Japan
- Tamagaki, Keiichi, Kyoto Prefectural University of Medicine, Kyoto, Japan
Background
The initial phenotypes of diabetic nephropathy are renal hypertrophy accompanying an increase in GFR , resulting in an increase in glucose reabsorption at proximal tubules. However, the detailed morphological changes and underlying mechanisms are not fully understood.
Methods
To investigate the proximal tubule-specific phenotypes in type 2 diabetic mice, we generated transgenic db/db mice carrying tamoxifen-inducible proximal tubule-specific tdTomato reporter genes (SLC34a1CreER/R26tdTomato). We isolated tubular epithelial cells by FACS from mice in which the proximal tubular epithelium was exclusively labeled by tdTomato, and evaluated the tubule-specific molecular mechanisms of the development of diabetic nephropathy. To assess the proliferation of tubular epithelial cells, we also performed lineage tracing analysis of single-labeled proximal tubular epithelial cells in db/db mice by low-dose tamoxifen injection.
Results
Histological analysis of 18-week-old diabetic mouse kidneys revealed expansion of the renal cortex and enlargement of the cross-sectional area in each tubule. The protein/DNA ratio, a marker of cellular hypertrophy, was not increased in FACS-isolated tubular epithelial cells from the diabetic mouse kidney. qPCR analysis revealed that SGLT2 and GLUT2 expression in isolated tubular epithelial cells was not increased in diabetic mice. Lastly, lineage tracing analysis of single-labeled proximal tubular epithelia cells revealed significant clonal expansion of the labeled epithelium in db/db mice, suggesting increased cell proliferation during the observational period.
Conclusion
Our study using a proximal tubule-specific reporter demonstrated that cell proliferation, rather than cellular hypertrophy, plays a role in the enlargement of the tubular lumen and subsequent kidney hypertrophy in early diabetic nephropathy. This suggests that the increase in glucose reabsorption under diabetic conditions is due to the proliferation of proximal tubular epithelial cells, which predominantly express SGLT2, and not to the overexpression of SGLT2 in individual cells.