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Updated: Sep 7, 2025
Comparative Proteomic Analysis of Whole Kidney, Medulla, and Cortical Tubules in Diabetic Pathogenesis of Kidney Injury in Mice
Published on: May 2, 2025
Mapping the single-cell transcriptomic response of murine diabetic kidney disease to therapies
Haojia Wu1, Romer Gonzalez Villalobos2, Xiang Yao3
1Division of Nephrology, Department of Medicine, Washington University, St. Louis, MO, USA.
Abstract:
Diabetic kidney disease (DKD) occurs in ∼40% of patients with diabetes and causes kidney failure, cardiovascular disease, and premature death. We analyzed the response of a murine DKD model to five treatment regimens using single-cell RNA sequencing (scRNA-seq). Our atlas of ∼1 million cells revealed a heterogeneous response of all kidney cell types both to DKD and its treatment. Both monotherapy and combination therapies targeted differing cell types and induced distinct and non-overlapping transcriptional changes. The early effects of sodium-glucose cotransporter-2 inhibitors (SGLT2i) on the S1 segment of the proximal tubule suggest that this drug class induces fasting mimicry and hypoxia responses. Diabetes downregulated the spliceosome regulator serine/arginine-rich splicing factor 7 (Srsf7) in proximal tubule that was specifically rescued by SGLT2i. In vitro proximal tubule knockdown of Srsf7 induced a pro-inflammatory phenotype, implicating alternative splicing as a driver of DKD and suggesting SGLT2i regulation of proximal tubule alternative splicing as a potential mechanism of action for this drug class.
Insights
Diabetic kidney disease (DKD) affects 40% of diabetes patients. This study reveals how SGLT2 inhibitors impact kidney cells and suggests their regulation of alternative splicing may be a key treatment mechanism.
Area of Science:
- Nephrology
- Genomics
- Pharmacology
Background:
- Diabetic kidney disease (DKD) affects approximately 40% of individuals with diabetes, leading to severe health complications.
- Understanding the cellular and molecular mechanisms of DKD and its treatment is crucial for improving patient outcomes.
Purpose of the Study:
- To investigate the heterogeneous cellular responses to DKD and various treatment regimens in a murine model.
- To elucidate the specific mechanisms of action for sodium-glucose cotransporter-2 inhibitors (SGLT2i) in DKD.
Main Methods:
- Utilized single-cell RNA sequencing (scRNA-seq) to analyze approximately one million cells from a murine DKD model.
- Examined the transcriptional changes in all kidney cell types under DKD conditions and in response to five different treatment strategies.
- Conducted in vitro experiments to assess the functional impact of specific gene alterations.
Main Results:
- DKD and its treatments induced heterogeneous transcriptional responses across all kidney cell types.
- Sodium-glucose cotransporter-2 inhibitors (SGLT2i) demonstrated early effects on proximal tubule cells, suggesting induction of fasting mimicry and hypoxia.
- SGLT2i specifically rescued the downregulation of serine/arginine-rich splicing factor 7 (Srsf7) in proximal tubules, a factor implicated in DKD pathogenesis.
Conclusions:
- Alternative splicing, particularly the regulation of Srsf7, is implicated as a driver of DKD.
- SGLT2i's potential mechanism of action involves the regulation of alternative splicing in proximal tubule cells.
- This study provides a comprehensive single-cell atlas of DKD and treatment responses, highlighting novel therapeutic targets.
