1. Integrative transcriptomic profiling of a mouse model of hypertension-accelerated diabetic kidney disease.
- Author
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Sembach FE, Ægidius HM, Fink LN, Secher T, Aarup A, Jelsing J, Vrang N, Feldt-Rasmussen B, Rigbolt KTG, Nielsen JC, and Østergaard MV
- Subjects
- Animals, Dependovirus metabolism, Disease Models, Animal, Female, Gene Expression Regulation, Kidney Cortex metabolism, Kidney Cortex pathology, Kidney Glomerulus metabolism, Kidney Glomerulus pathology, Mice, Inbred C57BL, Renin metabolism, Mice, Diabetic Nephropathies etiology, Diabetic Nephropathies genetics, Gene Expression Profiling, Hypertension complications
- Abstract
The current understanding of molecular mechanisms driving diabetic kidney disease (DKD) is limited, partly due to the complex structure of the kidney. To identify genes and signalling pathways involved in the progression of DKD, we compared kidney cortical versus glomerular transcriptome profiles in uninephrectomized (UNx) db/db mouse models of early-stage (UNx only) and advanced [UNxplus adeno-associated virus-mediated renin-1 overexpression (UNx-Renin)] DKD using RNAseq. Compared to normoglycemic db/m mice, db/db UNx and db/db UNx-Renin mice showed marked changes in their kidney cortical and glomerular gene expression profiles. UNx-Renin mice displayed more marked perturbations in gene components associated with the activation of the immune system and enhanced extracellular matrix remodelling, supporting histological hallmarks of progressive DKD in this model. Single-nucleus RNAseq enabled the linking of transcriptome profiles to specific kidney cell types. In conclusion, integration of RNAseq at the cortical, glomerular and single-nucleus level provides an enhanced resolution of molecular signalling pathways associated with disease progression in preclinical models of DKD, and may thus be advantageous for identifying novel therapeutic targets in DKD., Competing Interests: Competing interests F.E.S., H.M.Æ., J.C.N., T.S., M.V.Ø., K.T.G.R. and L.N.F. are employees of Gubra ApS. N.V. and J.J. are owners of Gubra ApS., (© 2021. Published by The Company of Biologists Ltd.)
- Published
- 2021
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