Publications by authors named "Andre Kraus"

7 Publications

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

J Mol Med (Berl) 2020 11 4;98(11):1547-1559. Epub 2020 Sep 4.

Department of Nephrology and Hypertension, Friedrich-Alexander-University Erlangen-Nuernberg, Ulmenweg 18, D - 91054, Erlangen, Germany.

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.
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http://dx.doi.org/10.1007/s00109-020-01964-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7591438PMC
November 2020

Cyst growth in ADPKD is prevented by pharmacological and genetic inhibition of TMEM16A in vivo.

Nat Commun 2020 08 28;11(1):4320. Epub 2020 Aug 28.

Department of Nephrology and Hypertension, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany.

In autosomal dominant polycystic kidney disease (ADPKD) multiple bilateral renal cysts gradually enlarge, leading to a decline in renal function. Transepithelial chloride secretion through cystic fibrosis transmembrane conductance regulator (CFTR) and TMEM16A (anoctamin 1) are known to drive cyst enlargement. Here we demonstrate that loss of Pkd1 increased expression of TMEM16A and CFTR and Cl secretion in murine kidneys, with TMEM16A essentially contributing to cyst growth. Upregulated TMEM16A enhanced intracellular Ca signaling and proliferation of Pkd1-deficient renal epithelial cells. In contrast, increase in Ca signaling, cell proliferation and CFTR expression was not observed in Pkd1/Tmem16a double knockout mice. Knockout of Tmem16a or inhibition of TMEM16A in vivo by the FDA-approved drugs niclosamide and benzbromarone, as well as the TMEM16A-specific inhibitor Ani9 largely reduced cyst enlargement and abnormal cyst cell proliferation. The present data establish a therapeutic concept for the treatment of ADPKD.
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http://dx.doi.org/10.1038/s41467-020-18104-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7455562PMC
August 2020

Lipid Peroxidation Drives Renal Cyst Growth through Activation of TMEM16A.

J Am Soc Nephrol 2019 02 3;30(2):228-242. Epub 2019 Jan 3.

Department of Physiology, University of Regensburg, Regensburg, Germany; and

Background: Transepithelial chloride secretion, through the chloride channels cystic fibrosis transmembrane conductance regulator (CFTR) and TMEM16A (anoctamin 1), drives cyst enlargement in polycystic kidney disease (PKD). Polycystic kidneys are hypoxic, and oxidative stress activates TMEM16A. However, mechanisms for channel activation in PKD remain obscure.

Methods: Using tissue samples from patients with autosomal dominant PKD, embryonic kidney cultures, and an MDCK cyst model, we assessed peroxidation of plasma membrane phospholipids in human and mouse polycystic kidneys. We also used electrophysiologic Ussing chamber and patch clamp experiments to analyze activation of TMEM16A and growth of renal cysts.

Results: Peroxidation of phospholipids in human and mouse kidneys as well as MDCK cysts is probably due to enhanced levels of reactive oxygen species. Lipid peroxidation correlated with increased cyst volume as shown in renal cultures and MDCK cysts in three-dimensional cultures. Reactive oxygen species and lipid peroxidation strongly activated TMEM16A, leading to depletion of calcium ion stores and store-operated calcium influx. Activation of TMEM16A- and CFTR-dependent chloride secretion strongly augmented cyst growth. Exposure to scavengers of reactive oxygen species, such as glutathione, coenzyme Q10, or idebenone (a synthetic coenzyme Q10 homolog), as well as inhibition of oxidative lipid damage by ferrostatin-1 largely reduced activation of TMEM16A. Inhibition of TMEM16A reduced proliferation and fluid secretion .

Conclusions: These findings indicate that activation of TMEM16A by lipid peroxidation drives growth of renal cysts. We propose direct inhibition of TMEM16A or inhibition of lipid peroxidation as potentially powerful therapeutic approaches to delay cyst development in PKD.
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http://dx.doi.org/10.1681/ASN.2018010039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6362630PMC
February 2019

HIF-1α promotes cyst progression in a mouse model of autosomal dominant polycystic kidney disease.

Kidney Int 2018 11 30;94(5):887-899. Epub 2018 Aug 30.

Department of Nephrology and Hypertension, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany. Electronic address:

Autosomal dominant polycystic kidney disease (ADPKD) is mainly caused by mutations of the PKD1 gene and characterized by growth of bilateral renal cysts. Cyst growth is accompanied by regional hypoxia and induction of hypoxia-inducible factor (HIF)-1α in cyst-lining epithelial cells. To determine the relevance of HIF-1α for cyst growth in vivo we used an inducible kidney epithelium-specific knockout mouse to delete Pkd1 at postnatal day 20 or 35 to induce polycystic kidney disease of different severity and analyzed the effects of Hif-1α co-deletion and HIF-1α stabilization using a prolyl-hydroxylase inhibitor. HIF-1α expression was enhanced in kidneys with progressive cyst growth induced by early Pkd1 deletion, but unchanged in the milder phenotype induced by later Pkd1 deletion. Hif-1α co-deletion significantly attenuated cyst growth in the severe, but not in the mild, phenotype. Application of a prolyl-hydroxylase inhibitor resulted in severe aggravation of the mild phenotype with rapid loss of renal function. HIF-1α expression was associated with induction of genes that mediate calcium-activated chloride secretion. Thus, HIF-1α does not seem to play a role in early cyst formation, but accelerates cyst growth during progressive polycystic kidney disease. This novel mechanism of cyst growth may qualify as a therapeutic target.
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http://dx.doi.org/10.1016/j.kint.2018.06.008DOI Listing
November 2018

P2Y2R is a direct target of HIF-1α and mediates secretion-dependent cyst growth of renal cyst-forming epithelial cells.

Purinergic Signal 2016 12 26;12(4):687-695. Epub 2016 Aug 26.

Department of Nephrology and Hypertension, Friedrich-Alexander University of Erlangen-Nürnberg, Ulmenweg 18, 91054, Erlangen, Germany.

Polycystic kidney diseases are characterized by numerous renal cysts that continuously enlarge resulting in compression of intact nephrons and tissue hypoxia. Recently, we have shown that hypoxia-inducible factor (HIF)-1α promotes secretion-dependent cyst expansion, presumably by transcriptional regulation of proteins that are involved in calcium-activated chloride secretion. Here, we report that HIF-1α directly activates expression of the purinergic receptor P2Y2R in human primary renal tubular cells. In addition, we found that P2Y2R is highly expressed in cyst-lining cells of human ADPKD kidneys as well as PKD1 orthologous mouse kidneys. Knockdown of P2Y2R in renal collecting duct cells inhibited calcium-dependent chloride secretion in Ussing chamber analyses. In line with these findings, knockdown of P2Y2R retarded cyst expansion in vitro and prevented ATP- and HIF-1α-dependent cyst growth. In conclusion, P2Y2R mediates ATP-dependent cyst growth and is transcriptionally regulated by HIF-1α. These findings provide further mechanistic evidence on how hypoxia promotes cyst growth.
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http://dx.doi.org/10.1007/s11302-016-9532-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5124009PMC
December 2016

Glucose promotes secretion-dependent renal cyst growth.

J Mol Med (Berl) 2016 Jan 3;94(1):107-17. Epub 2015 Sep 3.

Department of Nephrology and Hypertension, Friedrich-Alexander-University Erlangen-Nürnberg, Ulmenweg 18, 91054, Erlangen, Germany.

Unlabelled: Polycystic kidney diseases are characterized by the development of numerous bilateral renal cysts that continuously enlarge resulting in a decline of kidney function due to compression of intact nephrons. Cyst growth is driven by transepithelial chloride secretion which depends on both intracellular cAMP and calcium. Mechanisms that are involved in the regulation of the underlying secretory pathways remain incompletely understood. Here we show that glucose concentration has a strong impact on cyst growth of renal tubular cells within a collagen matrix as well as in embryonic kidneys deficient or competent for Pkd1. Glucose-dependent cyst growth correlates with the transcriptional induction of the calcium-activated chloride channel anoctamin 1 (ANO1) and its increased expression in the apical membrane of cyst-forming cells. Inhibition of ANO1 with the specific inhibitor CaCCinh-AO1 significantly decreases glucose-dependent cyst growth in both models. Ussing chamber analyses revealed increased apical chloride secretion of renal tubular cells upon exposure to high glucose medium which can also be inhibited by the use of CaCCinh-AO1. These data suggest that glycemic control may help to reduce renal cyst growth in patients with polycystic kidney disease.

Key Message: Renal cyst growth depends on glucose concentration in two in vitro cyst models. High glucose leads to upregulation of the calcium-activated chloride channel ANO1. High glucose promotes calcium-activated chloride secretion via ANO1. Glucose-dependent secretion can be inhibited by a specific inhibitor of ANO1.
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http://dx.doi.org/10.1007/s00109-015-1337-4DOI Listing
January 2016

Hypoxia inhibits nephrogenesis through paracrine Vegfa despite the ability to enhance tubulogenesis.

Kidney Int 2015 Dec 22;88(6):1283-1292. Epub 2015 Jul 22.

Department of Nephrology and Hypertension, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Erlangen, Germany.

Reduced nephron number predisposes to hypertension and kidney disease. Interaction of the branching ureteric bud and surrounding mesenchymal cells determines nephron number. Since oxygen supply may be critical for intrauterine development, we tested whether hypoxia and hypoxia-inducible factor-1α (HIF-1α) influence nephrogenesis. We found that HIF-1α is required for branching of MDCK cells. In addition, culture of metanephric mouse kidneys with ureteric bud cell-specific stabilization or knockout of HIF-1α revealed a positive impact of HIF-1α on nephrogenesis. In contrast, widespread stabilization of HIF-1α in metanephric kidneys through hypoxia or HIF stabilizers impaired nephrogenesis, and pharmacological HIF inhibition enhanced nephrogenesis. Several lines of evidence suggest an inhibitory effect through the hypoxia response of mesenchymal cells. HIF-1α was expressed in mesenchymal cells during nephrogenesis. Expression of the anti-branching factors Bmp4 and Vegfa, secreted by mesenchymal cells, was increased upon HIF stabilization. The conditioned medium from hypoxic metanephric kidneys inhibited MDCK branching, which was partially rescued by Vegfa antibodies. Thus, the effect of HIF-1α on nephrogenesis appears context dependent. While HIF-1α in the ureteric bud is of importance for proper branching morphogenesis, the net effect of hypoxia-induced HIF activation in the embryonic kidney appears to be mesenchymal cell-dependent inhibition of ureter branching.
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http://dx.doi.org/10.1038/ki.2015.214DOI Listing
December 2015