Introduction: Diabetic Kidney Disease (DKD) is a leading cause of end-stage kidney disease in developed countries. Injury to Proximal tubule (PT) cells is a hallmark of DKD. Hypothesis: We hypothesized that diabetic PTs undergo maladaptive metabolic reprogramming and that distinct damage-repair cell transcriptional trajectories precede structural damage as evidenced by histology. Methods: Single-nucleus (sn)RNAseq PT transcriptomes from 17 to 25-week-old Zucker Diabetic Fatty (ZDF: 21,470 cells) and non-diabetic Zucker lean (Control: 14,841 cells) rats were analyzed. Cell clusters were annotated based on markers expression levels (H: high, M: medium, L: low) as Subsegments 1 Lrp2H, Slc5a2H, Slc22a6H), subsegment 3 (PT-S3; Lrp2H, Slc5a2L, Slc5a10H), adaptive state (a-PT; Lrp2M), dedifferentiated (dd-PT; Lrp2L) and injured (inj-PT; Lrp2L, Kim1H, Il34H, Spp1H); and slingshot trajectory analysis applied. Blood chemistry and urinalysis were conducted, and kidney morphology was assessed using histology. Gene set enrichment analysis was performed using the Hallmark (H) gene sets from the Molecular Signatures Database (MSigDB). Results: ZDF rat shows proteinuria and increased blood urea nitrogen, along with elevated plasma glucose, cholesterol and triglycerides (p< 0.05; n=11). Compared to Control, ZDF showed an increased trend in interstitial fibrosis and tubular atrophy from 17 (n=4) to 25 (n=7) weeks, although this did not reach statistical significance. Cell distribution by state: ZDF: 71.9% mature PT (S1/S2, S3), 6.5% a-PT, 14.9% dd-PT, 6.7% inj-PT; and Control: 86% mature PT, 3.6% a-PT, 9.0% dd-PT, and 1.4% inj-PT. Slingshot analysis showed two trajectories: 1) inj-PT ↔ dd-PT ↔ a-PT ↔ PT-S1/S2; and 2) inj-PT ↔ dd-PT ↔ PT-S3. Hallmark pathway analysis revealed differences in metabolic programs between control and diabetic samples, along with enrichment of inflammatory signaling pathways in diabetes. Conclusions: transcriptional heterogeneity in PT populations during early DKD precedes histologically detectable structural damage, revealing segment-specific cellular responses that warrant further investigation with adequate statistical power. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.
Jadhav et al. (2026) studied this question.