Bile Acid Receptor Agonist Reverses Transforming Growth Factor-β1-Mediated Fibrogenesis in Human Induced Pluripotent Stem Cells-Derived Kidney Organoids.

Autor:	Yang X; Department of Pathology, Johns Hopkins University, Baltimore, Maryland., Delsante M; Department of Pathology, Johns Hopkins University, Baltimore, Maryland; Scuola di Specializione in Nefrologia, University of Parma, Parma, Italy., Daneshpajouhnejad P; Department of Pathology, Johns Hopkins University, Baltimore, Maryland., Fenaroli P; Department of Pathology, Johns Hopkins University, Baltimore, Maryland; Scuola di Specializione in Nefrologia, University of Parma, Parma, Italy., Mandell KP; Department of Pathology, Johns Hopkins University, Baltimore, Maryland., Wang X; Department of Biochemistry and Molecular and Cellular Biology, Georgetown University, Washington, DC., Takahashi S; Department of Biochemistry and Molecular and Cellular Biology, Georgetown University, Washington, DC., Halushka MK; Department of Pathology, Johns Hopkins University, Baltimore, Maryland., Kopp JB; Kidney Disease Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland., Levi M; Department of Biochemistry and Molecular and Cellular Biology, Georgetown University, Washington, DC., Rosenberg AZ; Department of Pathology, Johns Hopkins University, Baltimore, Maryland. Electronic address: arosen34@jhmi.edu.
Jazyk:	angličtina
Zdroj:	Laboratory investigation; a journal of technical methods and pathology [Lab Invest] 2024 May; Vol. 104 (5), pp. 100336. Date of Electronic Publication: 2024 Jan 22.
DOI:	10.1016/j.labinv.2024.100336
Abstrakt:	Chronic kidney disease progresses through the replacement of functional tissue compartments with fibrosis, a maladaptive repair process. Shifting kidney repair toward a physiologically intact architecture, rather than fibrosis, is key to blocking chronic kidney disease progression. Much research into the mechanisms of fibrosis is performed in rodent models with less attention to the human genetic context. Recently, human induced pluripotent stem cell (iPSC)-derived organoids have shown promise in overcoming the limitation. In this study, we developed a fibrosis model that uses human iPSC-based 3-dimensional renal organoids, in which exogenous transforming growth factor-β1 (TGF-β1) induced the production of extracellular matrix. TGF-β1-treated organoids showed tubulocentric collagen 1α1 production by regulating downstream transcriptional regulators, Farnesoid X receptor, phosphorylated mothers against decapentaplegic homolog 3 (p-SMAD3), and transcriptional coactivator with PDZ-binding motif (TAZ). Increased nuclear TAZ expression was confirmed in the tubular epithelium in human kidney biopsies with tubular injury and early fibrosis. A dual bile acid receptor agonist (INT-767) increased Farnesoid X receptor and reduced p-SMAD3 and TAZ, attenuating TGF-β1-induced fibrosis in kidney organoids. Finally, we show that TAZ interacted with TEA-domain transcription factors and p-SMAD3 with TAZ and TEA-domain transcription factor 4 coregulating collagen 1α1 gene transcription. In summary, we establish a novel, readily manipulable fibrogenesis model and posit a role for bile acid receptor agonism early in renal parenchymal fibrosis. (Copyright © 2024. Published by Elsevier Inc.)
Databáze:	MEDLINE
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