ASN's Mission

ASN leads the fight to prevent, treat, and cure kidney diseases throughout the world by educating health professionals and scientists, advancing research and innovation, communicating new knowledge, and advocating for the highest quality care for patients.

learn more

Contact ASN

1401 H St, NW, Ste 900, Washington, DC 20005

email@asn-online.org

202-640-4660

The Latest on Twitter

Kidney Week

Abstract: PO0676

Understanding Genetic Mechanisms of Diabetic Nephropathy at the Single-Cell Level

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

  • Guo, Jing, Duke-NUS Medical School Centre for Computational Biology, Singapore, Singapore
  • Nguyen, Mien, Cardiovascular and Metabolic Disorders Program, Duke-NUS Medical School, Singapore, Singapore
  • Yamaji, Takahiro, Cardiovascular and Metabolic Disorders Program, Duke-NUS Medical School, Singapore, Singapore
  • Azushima, Kengo, Yokohama City University Graduate School of Medicine, Department of Medical Science and Cardiorenal Medicine, Yokohama, Japan
  • Gurley, Susan B., Division of Nephrology and Hypertension, Oregon Health and Science University, Portland, Oregon, United States
  • Petretto, Enrico, Duke-NUS Medical School Centre for Computational Biology, Singapore, Singapore
  • Coffman, Thomas M., Cardiovascular and Metabolic Disorders Program, Duke-NUS Medical School, Singapore, Singapore
Background

Diabetic nephropathy (DN) is a leading cause of end-stage kidney disease worldwide. Susceptibility to DN is inherited but genetic determinants have not been clearly defined. We have previously described a mouse model combining Akita-Renin transgene (AR) that exhibits human DN features including albuminuria, glomerulosclerosis, and genetic predisposition. Susceptible (S) 129 strain AR mice develop overt DN whereas resistant (R) C57BL/6 AR mice are largely free of kidney damage.

Methods

We performed single-cell sequencing of glomerular cell obtained from the wildtype (WT) and AR mice from both S and R strains at 10 weeks of age before overt pathological abnormalities are present in S mice.

Results

A total of 60,682 cells were sequenced from the four conditions. Within the main glomerular cell lineages: podocytes, mesangial and endothelial cells, there were distinct functional clusters corresponding to the S and R strains (see figure). Within the S but not R strain, well-defined cell clusters derived from AR and WT were identifiable within podocytes and mesangial cells, while in other cell types, the impact of strain was much greater than diabetes and renin-angiotensin activation in driving differential gene expression. Gene networks defining the strain differences have potential functional relevance in the development of glomerular diseases. For example, in podocytes, gene networks related to cytoskeleton are activated in the R strain, whereas the S strain shows upregulated oxidative stress responses. A number of candidate genes identified in human DN and other inherited nephropathies are also differentially expressed on the S and R backgrounds.

Conclusion

Single-cell sequencing analysis of glomerular cells from a DN mouse model has identified cell-specific transcriptomic profiles linked to genetic susceptibility and resistance to DN, suggesting causal mechanisms. Substantial overlap with pathways and candidate genes linked to human DN suggest that this model can be useful for understanding genetic pathophysiology of DN in humans.

Funding

  • Government Support – Non-U.S.