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Kidney Week

Abstract: PO0896

Mapping the Response of Murine Diabetic Nephropathy to Therapy at Single-Cell Resolution

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

  • Wu, Haojia, Division of Nephrology, Washington University in Saint Louis, St. Louis, Missouri, United States
  • Gonzalez-Villalobos, Romer Andres, CVM Janssen Research & Development, LLC, Boston, Massachusetts, United States
  • Yao, Xiang, Tox LJ Janssen Research & Development, LLC, La Jolla, California, United States
  • Reilly, Dermot F., CVM Janssen Research & Development, LLC, Boston, Massachusetts, United States
  • Rankin, Matthew M., CVM Janssen Research & Development, LLC, Boston, Massachusetts, United States
  • Magnone, Maria chiara, CVM Janssen Research & Development, LLC, Boston, Massachusetts, United States
  • Myshkin, Eugene, CVM Janssen Research & Development, LLC, Boston, Massachusetts, United States
  • Breyer, Matthew Douglas, CVM Janssen Research & Development, LLC, Boston, Massachusetts, United States
  • Humphreys, Benjamin D., Division of Nephrology, Washington University in Saint Louis, St. Louis, Missouri, United States
Background

Diabetic Kidney Disease (DKD) is the major cause of kidney failure in the USA. Angiotensin blockers (ACEi/ARBs) and SGLT2 inhibitors (Canagliflozin) are only two approved therapies demonstrated to slow the progression of DKD.

Methods

We treated 40 diabetic db/db hypertensive (reninAAV) mice either with ACE inhibitor (lisinopril), an SGLT2 inhibitor (JNJ-39933673), a PPARg agonist (Rosiglitazone), or vehicle control (n=10/group). Each group received either 2 days or 2 weeks of treatment. We measured BP, glucose and UACR and collected kidneys for snRNA-seq.

Results

Drug treatment at 2d and 2 wks significantly reduced BP (lisinopril), glucose (Rosi and JNJ’3673), and Uacr (lisinopril, Rosi and JNJ’3673) from baseline demonstrating that either BP or glucose control independently impact Uacr in this model. We generated 1,324,051 single nucleus transcriptomes, detecting 2,028 unique genes/cell on average. Unbiased clustering identified 19 cell clusters representing all major cell types, including rare ones such as the JGA (3,614 cells), podocytes (8,851 cells) and macula densa (MD, 4,239 cells), with differential expression of hundreds of genes across all clusters. These expression changes included JGA renin expression which was strongly downregulated by exogenous renin in ReninAAV db/db mice compared to WT. SGLT2 expression was restricted to the S1 segment of the PT, and SGLT2 inhibition acutely downregulated S1 glucose transporter Slc2a5 (Glut5) perhaps reflecting compensation. Sglt1 expression was strongly downregulated in db/db reninAAV MD, and Sglt2 inhibition partially restored this expression. MD Sglt1 has been shown to act as a glucose sensor and, inhibit tubuloglomerular feedback, so increased expression would increase GFR.

Conclusion

This is the first comprehensive single cell transcriptional atlas of the effects of diabetic nephropathy treatments in a mouse model. Drug specific and overlapping gene expression patterns were identified and should help elucidate cell-specific mechanisms of therapeutic benefit.

Funding

  • Commercial Support