Shared and Distinct Renal Transcriptome Signatures in 3 Standard Mouse Models of Chronic Kidney Disease.

Autor:	Marstrand-Jørgensen AB; Gubra A/S, Hørsholm, Denmark, amj@gubra.dk., Sembach FE; Gubra A/S, Hørsholm, Denmark., Bak ST; Gubra A/S, Hørsholm, Denmark., Ougaard M; Gubra A/S, Hørsholm, Denmark., Christensen-Dalsgaard M; Gubra A/S, Hørsholm, Denmark., Rønn Madsen M; Gubra A/S, Hørsholm, Denmark., Jensen DM; Gubra A/S, Hørsholm, Denmark., Secher T; Gubra A/S, Hørsholm, Denmark.; Cell Imaging and Pharmacology, Cell Therapy R&D, Novo Nordisk A/S, Måløv, Denmark., Heimbürger SMN; Gubra A/S, Hørsholm, Denmark., Fink LN; Gubra A/S, Hørsholm, Denmark.; Biotherapeutics Screening, Ferring Pharmaceuticals A/S, Kastrup, Denmark., Hansen D; Department of Nephrology, Herlev-Gentofte Hospital, University of Copenhagen, Herlev, Denmark.; Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark., Hansen HH; Gubra A/S, Hørsholm, Denmark., Østergaard MV; Gubra A/S, Hørsholm, Denmark.; Novo Nordisk A/S, Måløv, Denmark., Christensen M; Gubra A/S, Hørsholm, Denmark., Dalbøge LS; Gubra A/S, Hørsholm, Denmark.
Jazyk:	angličtina
Zdroj:	Nephron [Nephron] 2024; Vol. 148 (7), pp. 487-502. Date of Electronic Publication: 2024 Feb 14.
DOI:	10.1159/000535918
Abstrakt:	Introduction: Several mouse models with diverse disease etiologies are used in preclinical research for chronic kidney disease (CKD). Here, we performed a head-to-head comparison of renal transcriptome signatures in standard mouse models of CKD to assess shared and distinct molecular changes in three mouse models commonly employed in preclinical CKD research and drug discovery. Methods: All experiments were conducted on male C57BL/6J mice. Mice underwent sham, unilateral ureter obstruction (UUO), or unilateral ischemic-reperfusion injury (uIRI) surgery and were terminated two- and 6-weeks post-surgery, respectively. The adenine-supplemented diet-induced (ADI) model of CKD was established by feeding with adenine diet for 6 weeks and compared to control diet feeding. For all models, endpoints included plasma biochemistry, kidney histology, and RNA sequencing. Results: All models displayed increased macrophage infiltration (F4/80 IHC) and fibrosis (collagen 1a1 IHC). Compared to corresponding controls, all models were characterized by an extensive number of renal differentially expressed genes (≥11,000), with a notable overlap in transcriptomic signatures across models. Gene expression markers of fibrosis, inflammation, and kidney injury supported histological findings. Interestingly, model-specific transcriptome signatures included several genes representing current drug targets for CKD, emphasizing advantages and limitations of the three CKD models in preclinical target and drug discovery. Conclusion: The UUO, uIRI, and ADI mouse models of CKD have significant commonalities in their renal global transcriptome profile. Model-specific renal transcriptional signatures should be considered when selecting the specific model in preclinical target and drug discovery. (© 2024 S. Karger AG, Basel.)
Databáze:	MEDLINE
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