Macrophage migration inhibitory factor is regulated by HIF-1α and cAMP and promotes renal cyst cell proliferation in a macrophage-independent manner

Autor: Johannes Schödel, Wajima Safi, Andre Kraus, Steffen Grampp, Bjoern Buchholz
Rok vydání: 2020
Předmět:
Fluorescent Antibody Technique
urologic and male genital diseases
Mice
0302 clinical medicine
Drug Discovery
Polycystic kidney disease
Cyclic AMP
Cyst
030212 general & internal medicine
Genetics (clinical)
Mice
Knockout
Macrophage migration inhibitory factor
0303 health sciences
Chemistry
Kidney Diseases
Cystic
female genital diseases and pregnancy complications
Cell biology
Intramolecular Oxidoreductases
Knockout mouse
Molecular Medicine
Original Article
Disease Susceptibility
ATP Binding Cassette Transporter 1
chemical and pharmacologic phenomena
Cell Line
03 medical and health sciences
Downregulation and upregulation
cAMP
medicine
otorhinolaryngologic diseases
Animals
Humans
Hypoxia-inducible factor 1α
ddc:610
Autocrine signalling
Transcription factor
Macrophage Migration-Inhibitory Factors
030304 developmental biology
Cell Proliferation
Dose-Response Relationship
Drug
Cell growth
Macrophages
Isoxazoles
medicine.disease
Hypoxia-Inducible Factor 1
alpha Subunit
biological factors
Disease Models
Animal
Gene Expression Regulation
Biomarkers
Zdroj: Journal of Molecular Medicine (Berlin, Germany)
ISSN: 1432-1440
Popis: Abstract Progressive cyst growth leads to decline of renal function in polycystic kidney disease. Macrophage migration inhibitory factor (MIF) was found to be upregulated in cyst-lining cells in a mouse model of polycystic kidney disease and to promote cyst growth. In addition, MIF can be secreted by tubular cells and may contribute to cyst growth in an autocrine manner. However, the underlying mechanisms leading to induction of MIF in cyst-lining cells remained elusive. Here, we demonstrate that hypoxia-inducible transcription factor (HIF) 1α upregulates MIF in cyst-lining cells in a tubule-specific PKD1 knockout mouse. Pharmacological stabilization of HIF-1α resulted in significant increase of MIF in cyst epithelial cells whereas tubule-specific knockout of HIF-1α prevented MIF upregulation. Identical regulation could be found for ABCA1, which has been shown to act as a transport protein for MIF. Furthermore, we show that MIF and ABCA1 are direct target genes of HIF-1α in human primary tubular cells. Next to HIF-1α and hypoxia, we found MIF being additionally regulated by cAMP which is a strong promotor of cyst growth. In line with these findings, HIF-1α- and cAMP-dependent in vitro cyst growth could be decreased by the MIF-inhibitor ISO-1 which resulted in reduced cyst cell proliferation. In conclusion, HIF-1α and cAMP regulate MIF in primary tubular cells and cyst-lining epithelial cells, and MIF promotes cyst growth in the absence of macrophages. In line with these findings, the MIF inhibitor ISO-1 attenuates HIF-1α- and cAMP-dependent in vitro cyst enlargement. Key messages • MIF is upregulated in cyst-lining cells in a polycystic kidney disease mouse model. • MIF upregulation is mediated by hypoxia-inducible transcription factor (HIF) 1α. • ABCA1, transport protein for MIF, is also regulated by HIF-1α in vitro and in vivo. • MIF is additionally regulated by cAMP, a strong promotor of cyst growth. • MIF-inhibitor ISO-1 reduces HIF-1α- and cAMP-dependent cyst growth.
Databáze: OpenAIRE
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