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

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 reveale...

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Published inCell metabolism Vol. 34; no. 7; pp. 1064 - 1078.e6
Main Authors Wu, Haojia, Gonzalez Villalobos, Romer, Yao, Xiang, Reilly, Dermot, Chen, Tao, Rankin, Matthew, Myshkin, Eugene, Breyer, Matthew D., Humphreys, Benjamin D.
Format Journal Article
LanguageEnglish
Published United States 05.07.2022
Subjects
Animals
Cardiovascular Diseases - drug therapy
Diabetes Mellitus, Type 2 - metabolism
Diabetic Nephropathies - drug therapy
Diabetic Nephropathies - genetics
Mice
Sodium-Glucose Transporter 2 Inhibitors - pharmacology
Sodium-Glucose Transporter 2 Inhibitors - therapeutic use
Transcriptome - genetics
drug response
kidney
chronic kidney disease
T2D
ACEi
FSGS
rosiglitazone
single-cell RNA-seq
SGLT2i
diabetes
hypertension
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Summary: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.
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H.W., M.D.B, R.G.V. and B.D.H. conceived, coordinated, and designed the study. H.W. performed experiments with contributions from R.G.V., and C.G. H.W., X.Y. and E.M. performed bioinformatic analysis. H.W., R.G.V., X.Y., D.R., T.C., M.R., E.M., M.D.B. and B.D.H. analyzed data. R.G.V., D.R., M.R., M.D.B. and B.D.H. designed experiments and edited the manuscript. H.W. and B.D.H. wrote the manuscript. All authors read and approved the final manuscript.
Author Contributions
ISSN:1550-4131
1932-7420
1932-7420
DOI:10.1016/j.cmet.2022.05.010