DOI: http://dx.doi.org/10.18203/2319-2003.ijbcp20204508

Hypoxia inducible factor stabilizers: a promising treatment for chronic kidney disease

Koushiki Mani, Johnny Karini, Kuntolika Mani, Ananya Amrit

Abstract


Anemia in chronic kidney disease (CKD) is a very common complication. The two main factors contributing to the development of anemia in CKD is decreased erythropoietin production and iron deficiency. Other factors that might play a role in the pathogenesis of renal anemia are: chronic inflammation leading to increased hepcidin, uremic toxins, and shorter red blood cell life span. The mainstay of treatment is iron supplementation, blood transfusion and erythropoietin stimulating agents (ESA). The discovery of hypoxia inducible factor (HIF) pathway has opened a new chapter in the treatment of anemia in CKD. The oxygen-sensitive HIF pathway plays a prominent role in the control of erythropoiesis and iron metabolism. HIF stabilizers are a new set of drugs that inhibits prolyl hydroxylase domain (PHD) proteins which are key regulators of HIF activity. Several such compounds are being developed to revolutionize the treatment of renal anemia.


Keywords


Anemia, Chronic kidney disease, Hypoxia-inducible factor, HIF stabilizers

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References


Babitt JL, Lin HY. Mechanisms of Anemia in CKD. J Am Soc Nephrol. 2012; 23:28:3458456.

Babitt JL, Lin HY. Molecular mechanisms of hepcidin regulation: Implications for the anemia of CKD. Am J Kidney Dis. 2010;55:726–41.

Semenza GL. Regulation of mammalian O2 homeostasis by hypoxia-inducible factor 1. Annu Rev Cell Dev Biol. 1999;15:551–78.

Kewley RJ, Whitelaw ML, Chapman-Smith A. The mammalian basic helix-loop-helix/PAS family of transcriptional regulators. Int J Biochem Cell Biol. 2004; 36:189–204.

Wenger RH, Stiehl DP, Camenisch G. Integration of oxygen signaling at the consensus HRE. Scien Sign. 2005;2005:12.

Hara S, Hamada J, Kobayashi C, Kondo Y and Imura N: Expression and characterization of hypoxia-inducible factor (HIF)-3alpha in human kidney: Suppression of HIF-mediated gene expression by HIF-3alpha. Biochem Biophys Res Commun. 2001;287:808–13.

Kaelin WG Jr, Ratcliffe PJ. Oxygen sensing by metazoans: the central role of the HIF hydroxylase pathway. Mol Cell. 2008;30:393–402.

Eschbach JW, Egrie JC, Downing MR, Browne JK, Adamson JW. Correction of the anemia of end-stage renal disease with recombinant human erythropoietin. Results of a combined phase I and II clinical trial. N Engl J Med. 1987;316:73-8.

Singh AK, Szczech L, Tang KL, Barnhart H, Sapp S, Wolfson M, Reddan D; CHOIR Investigators: Correction of anemia with epoetin alfa in chronic kidney disease. N Engl J Med. 2006;355:2085–98.

Solomon SD, Uno H, Lewis EF, Eckardt KU, Lin J, Burdmann EA, et al. Trial to Reduce Cardiovascular Events with Aranesp Therapy (TREAT) Investigators: Erythropoietic response and outcomes in kidney disease and type 2 diabetes. N Engl J Med. 2010;363:1146–55.

Liu Q, Davidoff O, Niss K, Haase VH. Hypoxia-inducible factor regulates hepcidin via erythropoietin-induced erythropoiesis. J Clin Invest. 2012; 122:4635–44.

Kautz L, Jung G, Valore EV, Rivella S, Nemeth E, Ganz T. Identification of erythroferrone as an erythroid regulator of iron metabolism. Nat Genet. 2014;46:678–84.

Dai Z, Li M, Wharton J, Zhu MM, Zhao YY. Prolyl-4 hydroxylase 2 (PHD2) deficiency in endothelial cells and hematopoietic cells induces obliterative vascular remodeling and severe pulmonary arterial hypertension in mice and humans through hypoxia-inducible factor-2α. Circulat. 2016;133:2447–58.

Tang H, Babicheva A, McDermott KM, Gu Y, Ayon RJ, Song S, et al. Endothelial HIF-2α contributes to severe pulmonary hypertension due to endothelial-to-mesenchymal transition. Americ J Physiol Lun Cellul Molecul Physiol. 2018;314(2):L256-75.

Liu S, Kumar SM, Martin JS, Yang R, Xu X. Snail1 mediates hypoxia-induced melanoma progression. Am J Pathol. 2011;179:3020–31.

Nagaraju GP, Bramhachari PV, Raghu G, El-Rayes BF. Hypoxia inducible factor-1alpha: Its role in colorectal carcinogenesis and metastasis. Canc lette. 2015;366(1):11–8.

Maxwell PH, Pugh CW, Ratcliffe PJ. Activation of the HIF pathway in cancer. Curr Opin Genet Dev. 2001;11(3):293–9.