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

Schley G, Scholz H, Kraus A, Hackenbeck T, Klanke B, Willam C, Wiesener MS, Heinze E, Burzlaff N, Eckardt KU, Buchholz B (2015)

Publication Type: Journal article

Publication year: 2015

Journal

Kidney International Nature Publishing Group: Open Access Hybrid Model Option A

Publisher: Nature Publishing Group: Open Access Hybrid Model Option A

Book Volume: 88

Pages Range: 1283-1292

Journal Issue: 6

DOI: 10.1038/ki.2015.214

Abstract

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 hypoxiainducible factor-1 alpha (HIF-1 alpha) influence nephrogenesis. We found that HIF-1 alpha is required for branching of MDCK cells. In addition, culture of metanephric mouse kidneys with ureteric bud cell-specific stabilization or knockout of HIF-1 alpha revealed a positive impact of HIF-1 alpha on nephrogenesis. In contrast, widespread stabilization of HIF-1 alpha 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-1 alpha 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-1 alpha on nephrogenesis appears context dependent. While HIF-1 alpha 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.

Authors with CRIS profile

Andre Kraus Department of Medicine 4 – Nephrology and Hypertension Carsten Willam Department of Medicine 4 – Nephrology and Hypertension Eva Waidmann Professur für Anorganische Chemie Nicolai Burzlaff Professur für Anorganische Chemie Kai-Uwe Eckardt Lehrstuhl für Innere Medizin IV Björn Buchholz Department of Medicine 4 – Nephrology and Hypertension

Involved external institutions

Charité - Universitätsmedizin Berlin DE Germany (DE)

How to cite

APA:

Schley, G., Scholz, H., Kraus, A., Hackenbeck, T., Klanke, B., Willam, C.,... Buchholz, B. (2015). Hypoxia inhibits nephrogenesis through paracrine Vegfa despite the ability to enhance tubulogenesis. Kidney International, 88(6), 1283-1292. https://dx.doi.org/10.1038/ki.2015.214

MLA:

Schley, Gunnar, et al. "Hypoxia inhibits nephrogenesis through paracrine Vegfa despite the ability to enhance tubulogenesis." Kidney International 88.6 (2015): 1283-1292.

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