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Cambridge Immunology Network

 

Research

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.

Publications

Key publications: 

Burrows N, Bashford-Rogers RJM, Bhute V, Penalver A, Ferdinand J, Stewart B, Smith FEG, Deobagkar-Lele M, Giudice G, Connor TM, Inaba A, Bergamaschi L, Smith S, Tran M, Petsalaki E, Lyons P, Espeli M, Huntly BJP, Smith KGC, Cornall RJ, Clatworthy MR, Maxwell PH. Dynamic regulation of Hypoxia-inducible factor-1α activity is essential for normal B cell development. Nature Immunology. 2020

Maxwell, PH. A new approach to treating renal anaemia. Nat Rev Nephrol. doi: 10.1038/s41581-019-0207-7. [Epub ahead of print] 2019

 

Stegen S, Laperre K, Eelen G, Rinaldi G, Fraisl P,Torrekens S, Van Looveren R, Loopmans S, Bultynck G, Vinckier S, Meersman F, Maxwell PH, Rai J, Weis M, Eyre DR, Ghesquiere B, Fendt SM, Carmeliet P, Carmeliet G. HIF-1α metabolically controls collagen synthesis and modification in chondrocytes. Nature. 565:511-515. 2019

 

Briston T, Stephen JM, Thomas LW, Esposito C, Chung YL, Syafruddin SE, Turmaine M, Maddalena LA, Greef B, Szabadkai G, Maxwell PH, Vanharanta S, Ashcroft M. VHL-Mediated Regulation of CHCHD4 and Mitochondrial Function. Front Oncol. 4;8:388. 2018

 

Young MD, Mitchell TJ, Vieira Braga FA, Tran MGB, Stewart BJ, Ferdinand JR, Collord G, Botting RA, Popescu DM, Loudon KW, Vento-Tormo R, Stephenson E, Cagan A, Farndon SJ, Del Castillo Velasco-Herrera M, Guzzo C, Richoz N, Mamanova L, Aho T, Armitage JN, Riddick ACP, Mushtaq I, Farrell S, Rampling D, Nicholson J, Filby A, Burge J, Lisgo S, Maxwell PH, Lindsay S, Warren AY, Stewart GD, Sebire N, Coleman N, Haniffa M, Teichmann SA, Clatworthy M, Behjati S. Single-cell transcriptomes from human kidneys reveal the cellular identity of renal tumors. Science. 10;361:594-599. 2018 Burrows N, Maxwell PH. Hypoxia and B cells. Exp Cell Res. 356(2):197-203. 2017

 

Kiriakidis S, Hoer SS, Burrows N, Biddlecome G, Khan M, Thinnes C, Schofield CJ, Rogers N, Botto M, Paleolog E, Maxwell PH. Complement C1q is hydroxylated by collagen proadvisorylyl 4 hydroxylase and is sensitive to off-target inhibition by prolyl hydroxylase domain inhibitors that stabilize hypoxia-inducible factor. Kidney International 92:900-908. 2017

 

Connor TM, Hoer SS, Mallet A, Gale DP, Gomez-Duran A, Posse V, Antrobus R, Moreno P, Sciacovelli M, Frezza C, Duff J, Sheerin NS, Sayer JA, Ashcroft M, Wiesener MS, Hudson G, Gustafsson CM, Chinnery PF, Maxwell PH. Mutations in mitochondrial DNA causing tubulointerstitial kidney disease. PLoS Genetics. 13:e1006620. 2017 Maxwell PH, Eckardt KU. HIF prolyl hydroxylase inhibitors for the treatment of renal anaemia and beyond. Nat Rev Nephrol. 12:157-68. 2016

 

Sciacovelli M, Gonçalves E, Johnson TI, Zecchini VR, da Costa AS, Gaude E, Drubbel AV, Theobald SJ, Abbo SR, Tran MG, Rajeeve V, Cardaci S, Foster S, Yun H, Cutillas P, Warren A, Gnanapragasam V, Gottlieb E, Franze K, Huntly B, Maher ER, Maxwell PH, Saez-Rodriguez J, Frezza C. Fumarate is an epigenetic modifier that elicits epithelial-to-mesenchymal transition. Nature. 537:544-547. 2016

 

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).

Professor  Patrick   Maxwell
Not available for consultancy

Affiliations