Oxygen sensing and renal diseases
All metazoans have a powerful control system based on hypoxia-inducible factor (HIF), which regulates transcription in response to changes in oxygenation. This operates in the physiological range, shaping many aspects of cellular and organismal behaviour. It also contributes to a range of disease processes, most notably clear cell renal cell carcinoma (CCRCC), the most common form of kidney cancer. The HIF pathway is constitutively activated in the great majority of CCRCC through biallelic inactivation of the VHL gene; this is because VHL acts as part of a ubiquitin E3 ligase complex which specifically recognises HIF-α subunits that are hydroxylated at specific prolyl residues. The prolyl hydroxylation is carried out by prolyl hydroxylase domain (PHD) enzymes. Inhibitors of the PHD enzymes are now being tested in humans by several companies for treatment of anaemia and ischaemic conditions. Our main avenues of research at present are: identifying methods of targeting VHL defective cells; seeking to characterise a VHL-independent pathway of HIF regulation; interrogating the role of HIF activation in aspects of adaptive immunity; determining the effect of PHD inhibitors on prolyl hydroxylation events in proteins other than HIF-α; and investigating the role of altered cellular metabolism in inherited renal diseases.
Burrows N, Cane G, Robson M, Gaude E, J Howat W, Szlosarek PW, Pedley RB, Frezza C, Ashcroft M, Maxwell PH. Hypoxia-induced nitric oxide production and tumour perfusion is inhibited by pegylated arginine deiminase (ADI-PEG20). Scientific Rep. Mar 14;6:22950 (2016).
Barriga, E.H., Maxwell, P.H., Reyes, A.E. and Mayor, R. The hypoxia factor Hif-1α controls neural crest chemotaxis and epithelial to mesenchymal transition. J. Cell Biol. 201, 759–776 (2013).
Xu, J., Wang. B., Xu, Y., Sun, L., Tian, W., Shukla, D., Barod, R., Grillari, J., Grillari-Voglauer, R., Maxwell, P.H. and Esteban, M.A. Epigenetic regulation of HIF-1α in renal cancer cells involves HIF-1α/2α binding to a reverse hypoxia-response element. Oncogene 31, 1065–1072 (2012).
Takeda, Y., Costa, S., Delamarre, E., Roncal, C., De Oliveira, R.L., Squadrito, M.L., Finisguerra, V., Bruyère, F., Deschoemaeker, S., Wenes, M., Hamm, A., Serneels, J., Magat, J., Bhattacharrya, T., Anisimov, A., Jordan, B.F., Alitalo, K., Maxwell, P., Gallez, B., Zhuang, Z.W., Saito, Y., Simons, M., De Palma, M. and Mazzone, M. Macrophage skewing by PHD2 haplodeficiency prevents ischemia by inducing arteriogenesis. Nature 479, 122–126 (2011).
Gale DP, de Jorge EG, Cook HT, Martinez-Barricarte R, Hadjisavvas A, McLean AG, Pusey CD, Pierides A, Kyriacou K, Athanasiou Y, Voskarides K, Deltas C, Palmer A, Fremeaux-Bacchi V, de Cordoba SR, Maxwell PH* & Pickering MC. Identification of a mutation in complement factor H-related protein 5 in patients of Cypriot origin with glomerulonephritis. Lancet 376, 794–801 (2010) *corresponding author + joint senior author.
Cantley J, Selman C, Shukla D, Abramov AY, Forstreuter F, Esteban MA, Claret M, Lingard SJ, Clements M, Harten SK, Asare-Anane H, Batterham RL, Herrera PL, Persaud SJ, Duchen MR, Maxwell PH* & Withers DJ*. Deletion of the von Hippel-Lindau gene in pancreatic beta cells impairs glucose homeostasis in mice. J. Clin. Invest. 119, 125–135 (2009) (*Joint corresponding author).
Aragonés J, Schneider M, Van Geyte K, Fraisl P, Dresselaers T, Mazzone M, Dirkx R, Zacchigna S, Lemieux H, Jeoung NH, Lambrechts D, Bishop T, Lafuste P, Diez-Juan A, Harten SK, Van Noten P, De Bock K, Willam C, Tjwa M, Grosfeld A, Navet R, Moons L, Vandendriessche T, Deroose C, Wijeyekoon B, Nuyts J, Jordan B, Silasi-Mansat R, Lupu F, Dewerchin M, Pugh C, Salmon P, Mortelmans L, Gallez B, Gorus F, Buyse J, Sluse F, Harris RA, Gnaiger E, Hespel P, Van Hecke P, Schuit F, Van Veldhoven P, Ratcliffe P, Baes M, Maxwell P & Carmeliet P. Deficiency or inhibition of oxygen sensor Phd1 induces hypoxia tolerance by reprogramming basal metabolism. Nature Genet. 40,170–180 (2008).