Many clinical observations suggest common mediators in the progression of kidney disease leading to eventual kidney failure. Among them, accumulating evidence emphasizes the role of chronic hypoxia in the tubulointerstitium in this role. When advanced, tubulointerstitial damage is associated with the loss of peritubular capillaries, impairing blood delivery. Associated interstitial fibrosis further impairs oxygen diffusion and supply to tubular and interstitial cells. This in turn exacerbates chronic hypoxia in this compartment, resulting in a vicious cycle. Both singly or together, glomerular injury and vasoconstriction of efferent arterioles due to an imbalance in vasoactive substances decrease post-glomerular peritubular capillary blood flow and contribute to chronic hypoxia in the tubulointerstitium. Anemia in kidney disease also plays a significant role in hypoxia of the kidney. Moreover, increased metabolic demand in tubular cells, as observed in glomerular hyperfiltration for example, can cause relative hypoxia. Importantly, these factors can affect the kidney before the appearance of significant pathological changes in the vasculature and predispose it to tubulointerstitial injury. Therapeutic approaches targeting chronic hypoxia in the kidney should be effective against a broad range of renal diseases. Recent studies have elucidated the mechanisms of hypoxia-induced transcription, giving hope for the development of novel therapeutic approaches against this final common pathway.

Brezis M, Rosen S: Hypoxia of the renal medulla – Its implications for disease. N Engl J Med 1995;332:647–655.
Fine LG, Bandyopadhay D, Norman JT: Is there a common mechanism for the progression of different types of renal diseases other than proteinuria? Towards the unifying theme of chronic hypoxia. Kidney Int 2000;75:S22–S26.
Kang DH, Kanellis J, Hugo C, Truong L, Anderson S, Kerjaschki D, Schreiner GF, Johnson RJ: Role of the microvascular endothelium in progressive renal disease. J Am Soc Nephrol 2002;13:806–816.
Eckardt K-U, Rosenberger C, Jürgensen JS, Wiesener MS: Role of hypoxia in the pathogenesis of renal disease. Blood Purif 2003;21:253–257.
Choi YJ, Chakraborty S, Nguyen V, Nguyen C, Kim BK, Shim SI, Suki WN, Truong LD: Peritubular capillary loss is associated with chronic tubulointerstitial injury in human kidney: Altered expression of vascular endothelial growth factor. Hum Pathol 2000;31:1491–1497.
Yuan H-T, Li X-Z, Pitera JE, Long DA, Woolf AS: Peritubular capillary loss after mouse acute nephrotoxicity correlates with down-regulation of vascular endothelial growth factor-A and hypoxia-inducible factor-1α. Am J Pathol 2003;163:2289–2301.
Matsumoto M, Tanaka T, Yamamoto T, Noiri E, Miyata T, Inagi R, Fujita T, Nangaku M: Hypoperfusion of peritubular capillaries induces chronic hypoxia before progression of tubulointerstitial injury in a progressive model of rat glomerulonephritis. J Am Soc Nephrol 2004;15:1574–1581.
Norman JT, Stidwill R, Singer M, Fine LG: Angiotensin II blockage augment renal cortical microvascular pO2 indicating a novel potential renoprotective action. Nephron Physiol 2003;94:39–46.
Manotham K, Tanaka T, Matsumoto M, Ohse T, Miyata T, Inagi R, Kurokawa K, Fujita T, Nangaku M: Evidence of tubular hypoxia in the early phase in the remnant kidney model. J Am Soc Nephrol 2004;15:1277–1288.
Iseki K, Ikemiya Y, Iseki C, Takishita S: Haematocrit and the risk of developing end-stage renal disease. Nephrol Dial Transplant 2003;18:899–905.
Keane WF, Brenner BM, de Zeeuw D, Grunfeld JP, McGill J, Mitch WE, Ribeiro AB, Shahinfar S, Simpson RL, Snapinn SM, Toto R. RENAAL Study Investigators: The risk of developing end-stage renal disease in patients with type 2 diabetes and nephropathy: The RENAAL study. Kidney Int 2003;63:1499–1507.
Ries M, Basseau F, Tyndal B, Jones R, Deminière C, Catargi B, Combe C, Moonen CWT, Grenier N: Renal diffusion and BOLD MRI in experimental diabetic nephropathy. J Magn Reson Imaging 2003;17:104–113.
Norman JT, Orphanides C, Garcia P, Fine LG: Hypoxia-induced changes in extracellular matrix metabolism in renal cells. Exp Nephrol 1999;7:463–469.
Norman JT, Clark IM, Garcia PL: Hypoxia promotes fibrogenesis in human renal fibroblasts. Kidney Int 2000;58:2351–2366.
Manotham K, Tanaka T, Matsumoto M, Ohse T, Inagi R, Miyata T, Kurokawa K, Fujita T, Ingelfinger JR, Nangaku M: Transdifferentiation of cultured tubular cells induced by hypoxia. Kidney Int 2004;65:871–880.
Tanaka T, Hanafusa N, Ingelfinger JR, Ohse T, Fujita T, Nangaku M: Hypoxia induces apoptosis in SV40-immortalized rat proximal tubular cells through the mitochondrial pathways, devoid of HIF-1-mediated upregulation of Bax. Biochem Biophys Res Commun 2003;309:222–231.
Kang DH, Hughes J, Mazzali M, Schreiner GF, Johnson RJ: Impaired angiogenesis in the remnant kidney model: II. Vascular endothelial growth factor administration reduces renal fibrosis and stabilizes renal function. J Am Soc Nephrol 2001;12:1448–1457.
Kunter U, Rong S, van Roeyen C, Milovanceva-Popovska M, Ostendorf T, Jahnen-Dechent W, Gröne H-J, Imai E, Floege J: Systemic overexpression of VEGF165 aggravates mesangioproliferative nephritis in rats (abstract). Nephrol Dial Transplant 2003;18(suppl 4):569.
Wiesener MS, Maxwell PH: HIF and oxygen sensing: as important to life as the air we breathe? Ann Med 2003;35:183–190.
Maxwell P: HIF-1: An oxygen response system with special relevance to the kidney. J Am Soc Nephrol 2003;14:2712–2722.
Wiesener MS, Jürgensen JS, Rosenberger C, Scholze CK, Hörstrup JH, Warnecke C, Mandriota S, Bechmann I, Frei UA, Pugh CW, Ratcliffe PJ, Bachmann S, Maxwell PH, Eckardt K-U: Widespread hypoxia-inducible expression of HIF-2alpha in distinct cell populations of different organs. FASEB J 2003;17:271–273.
Warnecke C, Griethe W, Weidemann A, Jürgensen JS, Willam C, Bachmann S, Ivashchenko Y, Wagner I, Frei U, Wiesener M, Eckardt K-U: Activation of the hypoxia-inducible factor-pathway and stimulation of angiogenesis by application of prolyl hydroxylase inhibitors. FASEB J 2003;17:1186–1188.
Vincent KA, Shyu KG, Luo Y, Magner M, Tio RA, Jiang C, Goldberg MA, Akita GY, Gregory RJ, Inner JM: Angiogenesis is induced in a rabbit model of hindlimb ischemia by naked DNA encoding an HIF-1alpha/VP16 hybrid transcription factor. Circulation 2000;102:2255–2261.
Shyu KG, Wang MT, Wang BW, Chang CC, Leu JG, Kuan P, Chang H: Intramyocardial injection of naked DNA encoding HIF-1alpha/VP16 hybrid to enhance angiogenesis in an acute myocardial infarction model in the rat. Cardiovasc Res 2002;54:576–583.
Michaud SE, Menard C, Guy LG, Gennaro G, Rivard A: Inhibition of hypoxia-induced angiogenesis by cigarette smoke exposure: Impairment of the HIF-1alpha/VEGF pathway. FASEB J 2003;17:1150–1152.
Manotham K, Tanaka T, Ohse T, Kojima I, Miyata T, Inagi R, Fujita T, Nangaku M: A biological role of HIF-1 in the renal medulla and its therapeutic implications. Submitted.
Matsumoto M, Makino Y, Tanaka T, Tanaka H, Ishizaka N, Noiri E, Fujita T, Nangaku M: Induction of renoprotective gene expression by cobalt ameliorates ischemic injury of the kidney in rats. J Am Soc Nephrol 2003;14:1825–1832.
You do not currently have access to this content.