Abstract: FR-PO0168
Targeted Proximal Tubule Injury Drives Secondary Glomerular Damage with Nodular Glomerulosclerosis in a Novel Model of Diabetic Kidney Disease
Session Information
- Diabetic Kidney Disease: Metabolic, Mitochondrial, and Inflammatory Mechanisms
October 23, 2026 | Location: Exhibit Hall A, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Cardiovascular-Kidney-Metabolic Health
- 601 Cardiovascular-Kidney-Metabolic Health: Basic
Authors
- Uchida, Yushi, Division of Renal Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, United States
- Chang, Jae Hyung, Division of Nephrology, Department of Medicine, Columbia University Medical Center, New York, New York, United States
- Li, Jiahua, Division of Renal Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, United States
- Suzuki, Tomohisa, Otsuka Pharmaceutical Factory, Inc., Naruto, Tokushima, Japan
- Takakura, Ayumi, Division of Renal Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, United States
- Ichimura, Takaharu, Division of Renal Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, United States
- Bonventre, Joseph V., Division of Renal Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, United States
Background
Diabetic kidney disease (DKD) has traditionally been regarded as a glomerulus-centered disorder with secondary tubulointerstitial disease. It is known, however, that tubulointerstitial injury predicts disease progression. We hypothesized that primary proximal tubule (PT) injury under diabetic conditions promotes interstitial inflammation, vascular rarefaction and secondary glomerular damage. DKD animal models are limited by modest functional impairment, prolonged time to attain a partial phenotype, and specialized genetic manipulation that does not mimic what naturally occurs in patients.
Methods
We generated Akita mice (model of Type 1 diabetes) that carried the renal epithelial cell-specific Six2Cre allele and the Cre-inducible simian diphtheria toxin receptor (DTR) transgene. Mice were subjected to unilateral nephrectomy and fed a high-fat diet. Targeted tubular injury was induced in these Akita mice with the DTR in renal epithelial cells (Akita DTRrec), as well as Akita and non-diabetic mice carrying the DTR, with a single sublethal dose of diphtheria toxin (DT). GFR, albuminuria, histopathology, and injury markers were evaluated longitudinally.
Results
DT-treated male Akita DTRrec mice developed sustained albuminuria compared with DT-treated WT, DTRrec, and Akita control mice. This was accompanied by persistent upregulation of the PT injury marker KIM-1 in both kidney tissue and urine. At 10 weeks after DT injection, Akita DTRrec mice exhibited renal dysfunction associated with tubular injury, as evidenced by reduced measured GFR. Histological analysis at 4 days after the DT revealed PT injury. At 10 weeks there was loss of WT1 and nephrin expression, nodular glomerular sclerosis in a Kimmelstiel-Wilson pattern seen in humans, interstitial collagen deposition, tubular atrophy, vascular rarefaction, and infiltration of macrophages and αSMA-positive myofibroblasts.
Conclusion
These findings demonstrate that PT injury, in the setting of diabetes and high lipid diet, promotes secondary glomerular injury and accelerated fibrotic remodeling. Our study supports tubular injury as a key driver of both interstitial and glomerular disease progression in DKD. Since tubular injury is common in individuals with diabetes, this model may be useful to better understanding pathophysiological mechanisms and evaluate potential therapeutic agents.
Funding
- NIDDK Support