Department of Nephrology and Hypertension, Friedrich-Alexander-University Erlangen-Nuernberg, Ulmenweg 18, D - 91054, Erlangen, Germany.
Pluripotency for Organ Regeneration, Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Technology (BIST), Barcelona, Spain.
J Mol Med (Berl). 2020 Nov;98(11):1547-1559. doi: 10.1007/s00109-020-01964-1. Epub 2020 Sep 4.
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.
多囊肾病中，囊肿的进行性生长导致肾功能下降。在多囊肾病的小鼠模型中发现，巨噬细胞移动抑制因子（MIF）在囊肿衬里细胞中上调，并促进囊肿生长。此外，MIF 可以由管状细胞分泌，并可能以自分泌的方式促进囊肿生长。然而，导致囊肿衬里细胞中 MIF 诱导的潜在机制仍不清楚。在这里，我们证明缺氧诱导转录因子（HIF）1α在肾小管特异性 PKD1 敲除小鼠的囊肿衬里细胞中上调 MIF。HIF-1α 的药理学稳定导致囊上皮细胞中 MIF 的显著增加，而肾小管特异性 HIF-1α 的敲除阻止了 MIF 的上调。对于 ABCA1 也可以发现相同的调节，ABCA1 已被证明是 MIF 的转运蛋白。此外，我们表明 MIF 和 ABCA1 是人类原代肾小管细胞中 HIF-1α 的直接靶基因。除了 HIF-1α 和缺氧之外，我们还发现 MIF 还受到 cAMP 的额外调节，cAMP 是囊肿生长的强烈促进剂。与这些发现一致，HIF-1α 和 cAMP 依赖性体外囊肿生长可以通过 MIF 抑制剂 ISO-1 减少，从而减少囊肿细胞增殖。总之，HIF-1α 和 cAMP 调节原代肾小管细胞和囊肿衬里上皮细胞中的 MIF，并且在没有巨噬细胞的情况下，MIF 促进囊肿生长。与这些发现一致，MIF 抑制剂 ISO-1 减弱了 HIF-1α 和 cAMP 依赖性的体外囊肿扩大。
在多囊肾病小鼠模型中，MIF 在囊肿衬里细胞中上调。
MIF 的上调是由缺氧诱导转录因子（HIF）1α介导的。
ABCA1，MIF 的转运蛋白，在体外和体内也受 HIF-1α 调节。
MIF 还受到 cAMP 的额外调节，cAMP 是囊肿生长的强促进剂。
MIF 抑制剂 ISO-1 减少了 HIF-1α 和 cAMP 依赖性的囊肿生长。
