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Germline mutations in the gene encoding the Krebs cycle enzyme Fumarate hydratase (FH) predispose to hereditary leiomyomatosis, renal cysts and type Ⅱ papillary and collecting duct renal cancer.Previous studies have demonstrated that FH-deficient tumours and cells accumulate fumarate and express high levels of hypoxia inducible factor (HIF)-1 α.Fumarate mediated inhibition of the HIF prolyl hydroxylase enzymes (PHDs) and prevention of HIFα hydroxylation and subsequent degradation has been proposed as a possible mechanism to explain this constitutive HIF expression.Previously, we have generated Fh 1 (murine orthologue of FH) conditional knockout mice that develop proliferative renal cystic disease.