Abstract: SA-PO0303
Transcriptional Reprogramming of Proximal Tubules in Type 2 Diabetes Precedes Structural Damage
Session Information
- Diabetic Kidney Disease: Basic and Translational Science Advances - 2
November 08, 2025 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Diabetic Kidney Disease
- 701 Diabetic Kidney Disease: Basic
Authors
- Jadhav, Darshan, Case Western Reserve University School of Medicine, Cleveland, Ohio, United States
- Kim, Najeong, Case Western Reserve University School of Medicine, Cleveland, Ohio, United States
- Rivoira, Maria Angelica, Instituto de Investigaciones en Ciencias de la Salud, Córdoba, Córdoba Province, Argentina
- Repossi, Gastón, Instituto de Investigaciones en Ciencias de la Salud, Córdoba, Córdoba Province, Argentina
- Garcia, Nestor H., Instituto de Investigaciones en Ciencias de la Salud, Córdoba, Córdoba Province, Argentina
- Gonzalez-Vicente, Agustin, Case Western Reserve University School of Medicine, Cleveland, Ohio, United States
Background
A better molecular understanding of Diabetic Kidney Disease (DKD) could uncover disease subtypes to aid in the development of new therapeutics. We hypothesized that “proximal tubule (PT) transcriptional alterations in type II diabetes occur before structural abnormalities become evident”.
Methods
Paired kidney single-nucleus (sn)RNAseq and histology data were generated from 17-week old Zucker Diabetic Fatty and Control rats (n=4); recovering 12250 and 9510 PT transcriptomes respectively. PTs mapped to five distinct clusters (Figure1)
Results
Diabetic rats showed proteinuria and increased blood urea nitrogen. Slingshot analysis (Figure2) showed two trajectories: 1) PT-S1/S2→DD-early→DD-late→Injured, and 2) PT-S3→DD-early→DD-late→Injured. Histologic analysis revealed no increase in interstitial fibrosis or tubular atrophy in diabetic, nor evidence of interstitial inflammation or exudative lesions. However, cell stage distributions differed as follows: 1) Diabetic: 65% Basal Stage (PT-S1/S2 & PT-S3), 19% DD-early, 3% DD-late, and 12% Injured; and 2) Control: 90% Basal Stage, 5% DD-early, 3% DD-late, and 2% Injured.
Conclusion
The observed shifts in cell state distribution indicate that transcriptional alterations in diabetic PTs precede evidence of structural damage, underscoring the sensitivity of these analyses for studying DKD progression.
Funding
- NIDDK Support