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

Haojia Wu, Romer Gonzalez Villalobos, Xiang Yao, Dermot Reilly, Tao Chen, Matthew Rankin, Eugene Myshkin, Matthew D. Breyer, Benjamin D. Humphreys

Research output: Contribution to journalArticlepeer-review

78 Scopus citations

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.

Original languageEnglish
Pages (from-to)1064-1078.e6
JournalCell metabolism
Volume34
Issue number7
DOIs
StatePublished - Jul 5 2022

Keywords

  • ACEi
  • FSGS
  • SGLT2i
  • T2D
  • chronic kidney disease
  • diabetes
  • drug response
  • hypertension
  • kidney
  • rosiglitazone
  • single-cell RNA-seq

Fingerprint

Dive into the research topics of 'Mapping the single-cell transcriptomic response of murine diabetic kidney disease to therapies'. Together they form a unique fingerprint.

Cite this