Mapping the single-cell transcriptomic response of murine diabetic kidney disease to therapies

• DOI: 10.1016/j.cmet.2022.05.010
• Publication Date: 2022-06-15T14:39:15Z
• Authors: Haojia Wu; Romer Gonzalez Vi...; Xiang Yao; Dermot Reilly; Tao Chen; Matthew Rankin; Eugene Myshkin; Matthew D. Breyer; Benjamin D. Humph...
• Keywords: 0303 health sciences; ICTS (Institute of Clinical and Translational Sciences); 3. Good health; Mice; 03 medical and health sciences; Diabetes Mellitus, Type 2; Cardiovascular Diseases; Diabetes Mellitus; Medicine and Health Sciences; Animals; Diabetic Nephropathies; Transcriptome; Sodium-Glucose Transporter 2 Inhibitors; Type 2

Diabetic kidney disease (DKD) occurs in ∼40% of patients with diabetes and causes failure, cardiovascular disease, premature death. We analyzed the response a murine DKD model to five treatment regimens using single-cell RNA sequencing (scRNA-seq). Our atlas ∼1 million cells revealed heterogeneous all cell types both its treatment. Both monotherapy combination therapies targeted differing induced distinct non-overlapping transcriptional changes. The early effects sodium-glucose cotransporter-2 inhibitors (SGLT2i) on S1 segment proximal tubule suggest that this drug class induces fasting mimicry hypoxia responses. Diabetes downregulated spliceosome regulator serine/arginine-rich splicing factor 7 (Srsf7) was specifically rescued by SGLT2i. In vitro knockdown Srsf7 pro-inflammatory phenotype, implicating alternative as driver suggesting SGLT2i regulation potential mechanism action for class.