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.
Highlights
Autosomal dominant polycystic kidney disease (ADPKD) is the most common potentially lethal monogenic disorder affecting approximately 1:1000 [1]
Tubular deletion of PKD1 was induced at postnatal days 35–37 which resulted in a slowly progressing polycystic renal phenotype which did not result in hypoxia or consecutive induction of hypoxiainducible transcription factor (HIF)-1α as shown previously [15]
We tested renal cysts within kidney tissue obtained from the named mouse model for ICA- and HIF-1αdependent effects on migration inhibitory factor (MIF) as well as ABCA1 expression by immunohistochemistry
Summary
Autosomal dominant polycystic kidney disease (ADPKD) is the most common potentially lethal monogenic disorder affecting approximately 1:1000 [1]. ADPKD is mainly characterized by the development of fluid-filled cysts originating from tubular epithelial cells in both kidneys. Cyst growth and disease progression have been attributed to several mechanisms, including cyst cell. J Mol Med (2020) 98:1547–1559 proliferation, transepithelial fluid transport into the cysts’ lumina, macrophage-dependent inflammation, and extracellular matrix deposition [3,4,5,6]. Cyst enlargement has been associated with interstitial inflammation reflected by macrophage infiltration resulting in decline of renal function [7, 8]. Macrophage depletion in an ADPKD mouse model resulted in smaller cysts, less cyst cell proliferation, and improved renal function [7, 8]
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