skip to content

Cambridge Institute for Medical Research


Oxygen sensing and renal diseases

General audience summary:
Our bodies have careful controls in place to determine how cells react to oxygen deprivation or hypoxia. If oxygen levels are too low, a tissue must quickly respond by changing its behaviour, such as changing which fuel it uses or growing more blood vessels. This is mediated by turning genes on and off. We study the control of this response to oxygen by master regulators called the ‘hypoxia-inducible factors’. In particular, we focus on how these factors are themselves kept under tight control, their importance in oxygen sensing during development and in the immune system, as well as how they can cause specific types of kidney cancers.

Strategic CIMR theme: Rare Genetic Diseases

Funding: Wellcome Trust, NIHR

Research Group members: Natalie Burrows, James McCaffery, Ana Penalver Alonso


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.


Key publications: 

Burrows N et al. Dynamic regulation of hypoxia-inducible factor-1α activity is essential for normal B cell development. Nature Immunology (2020) IN PRESS 

Burrows N & Maxwell PH. Hypoxia and B cells. Exp. Cell Res. 356, 197-203 (2017).

Kiriakidis S et al. Complement C1q is hydroxylated by collagen prolyl 4 hydroxylase and is sensitive to off-target inhibition by prolyl hydroxylase domain inhibitors that stabilize hypoxia-inducible factor. Kidney Int. (2017).

Connor TM et al. Mutations in mitochondrial DNA causing tubulointerstitial kidney disease. PLoS Genet. (2017).

Sciacovelli M et al. 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).

Regius Professor of Physic
Head of the School of Clinical Medicine

Contact Details
01223 336738 (PA)
Takes PhD students
Available for consultancy


Departments and institutes: