Kidney Week

Abstract: FR-PO0294

Hypertension Drives Inflammatory and Glomerular Disease Progression in Renin-Adeno-Associated Virus (AAV) Induced Diabetic Nephropathy

Session Information

• Diabetic Kidney Disease: Basic and Translational Science Advances - 1
  November 07, 2025 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Diabetic Kidney Disease

• 701 Diabetic Kidney Disease: Basic

Authors

• Huynh Cong, Evelyne, Evotec International GmbH, Göttingen, NDS, Germany

Evelyne Huynh Cong, PhD

• Nordlohne, Johannes, Evotec International GmbH, Göttingen, NDS, Germany

Johannes Nordlohne, PhD

• Schoening, Janne M, Evotec International GmbH, Göttingen, NDS, Germany

Janne M Schoening, DVM

• Balsamo, Anaïs, Evotec International GmbH, Göttingen, NDS, Germany

Anaïs Balsamo, MSc

• Lomow, Alexander, Evotec International GmbH, Göttingen, NDS, Germany

Alexander Lomow

• Guhl, Anna, Evotec International GmbH, Göttingen, NDS, Germany

Anna Guhl, MSc

• Schoeber, Claudia Joanna, Evotec International GmbH, Göttingen, NDS, Germany

Claudia Joanna Schoeber, MSc

• Veenhuis, Alva Lina, Evotec International GmbH, Göttingen, NDS, Germany

Alva Lina Veenhuis, MSc

• Gerdes, Jantje M, Evotec International GmbH, Göttingen, NDS, Germany

Jantje M Gerdes, PhD

Background

Long-term complications of diabetes include diabetic kidney disease (DKD), which is the leading cause of end-stage renal disease. Hypertension induction via Renin-AAV injection in db/db-uninephrectomized (uNx) mice was carried out to set up our accelerated DKD (aDKD) model. Mice develop exacerbate proteinuria and severe glomerular lesions quantified by automated glomerulosclerosis (GS) scoring method. Using flow cytometry, we characterized the inflammatory response and showed its increased in kidney and peripheral blood.

Methods

8 weeks old db/db mice underwent uNx and received 2 weeks later an i.v. injection of LacZ-AAV or Renin-AAV (low or high dose) to induce hypertension. Six weeks after uNx, mice were either treated with lisinopril or not. Organs were harvested 14 weeks after uNx. Kidneys were homogenized into single cell suspensions for flow cytometry analysis. A gating strategy was deployed to dissect mononuclear phagocytes subsets using cell markers (Cd11b, Cd11c, F4/80). Kidney sections were PAS-stained, digitized and processed into our AI-assisted algorithm. Over 5000 glomeruli were screened and cross-checked by a board-certified veterinary pathologist for GS evaluation.

Results

For both doses of Renin-AAV, mice develop massive proteinuria 6 weeks after uNx, which progresses over time up to 1.6x10⁴ µg/mg.
We developed an automated image analysis algorithm that detects Renin-AAV-induced sclerotic lesions in 39.4% of the analyzed glomeruli including 12,9% with severe injury (GS score ≥ 3). Treatment with lisinopril lowers uACR and reduces the percentage of sclerotic glomeruli to 13% (GS score ~ 1). Flow cytometry analysis of blood reveals a shift of peripheral monocytes towards more Ly6C+ inflammatory phenotype upon Renin-AAV-injection, then rescued by lisinopril. While neutrophils in kidney are unaffected, there is a positive correlation between levels of monocytes/macrophages and dendritic cells and hypertension.

Conclusion

We generated our aDKD model and characterized its phenotype. These mice present massive proteinuria, severe GS lesions, and more inflammatory cells in blood and kidney, all reversible upon lisinopril treatment. Our data suggests that our model is suitable for mono/combined treatment therapies for DKD preclinical trials.

Funding

• Commercial Support – Evotec

Digital Object Identifier (DOI)

• doi: 10.1681/ASN.2025q3cncbqh