Chronic hypoxia as a mechanism of progression of chronic kidney diseases: from hypothesis to novel therapeutics

被引:412
作者
Fine, Leon G. [2 ]
Norman, Jill T. [1 ]
机构
[1] UCL, Dept Med, Ctr Nephrol, Royal Free & Univ Coll Med Sch, London NW3 2PF, England
[2] Cedars Sinai Med Ctr, Dept Biomed Sci, Los Angeles, CA 90048 USA
基金
英国医学研究理事会; 美国国家卫生研究院;
关键词
chronic kidney disease; peritubular capillaries; hypoxia; fibrosis; hypoxia-inducible factors;
D O I
10.1038/ki.2008.350
中图分类号
R5 [内科学]; R69 [泌尿科学(泌尿生殖系疾病)];
学科分类号
1002 ; 100201 ;
摘要
In chronic kidney disease, functional impairment correlates with tubulointerstitial fibrosis characterised by inflammation, accumulation of extracellular matrix, tubular atrophy and rarefaction of peritubular capillaries. Loss of the microvasculature implies a hypoxic milieu and suggested an important role for hypoxia when the "chronic hypoxia hypothesis'' was proposed a decade ago as an explanation for the progressive nature of fibrosis. Recent data in man provide evidence of decreased renal oxygenation in chronic kidney disease while more direct support for a causal role comes from data in rodent models showing that the decline in renal oxygenation precedes matrix accumulation, suggesting hypoxia may both initiate and promote the fibrotic response. Indeed, in vitro studies show that hypoxia can induce pro-fibrotic changes in tubulointerstitial cells. Additional postulated roles for hypoxia in chronic kidney disease are the sustaining of the inflammatory response, the recruitment, retention and differentiation towards a pro-fibrotic phenotype of circulating progenitor cells and the alteration of the function of intrinsic stem cell populations. Given that accumulating data suggests that chronic hypoxia is a final common pathway to end-stage renal disease, therapeutic strategies that target hypoxia may be of benefit in retarding progression. Normalisation of microvascular tone, administration of pro-angiogenic factors to restore microvasculature integrity, activation of hypoxia-inducible transcription factors and hypoxia-mediated targeting and mobilisation of progenitor cells are all potential targets for future therapy. The limited success of existing strategies in retarding chronic kidney disease mandates that these new avenues of treatment be explored.
引用
收藏
页码:867 / 872
页数:6
相关论文
共 36 条
[1]   Endothelial/pericyte interactions [J].
Armulik, A ;
Abramsson, A ;
Betsholtz, C .
CIRCULATION RESEARCH, 2005, 97 (06) :512-523
[2]   Involvement of hypoxia-inducible transcription factors in polycystic kidney disease [J].
Bernhardt, Wanja Michael ;
Wiesener, Michael Sean ;
Weidemann, Alexander ;
Schmitt, Roland ;
Weichert, Wilko ;
Lechler, Philipp ;
Campean, Valentina ;
Ong, Albert Chee Meng ;
Willam, Carsten ;
Gretz, Norbert ;
Eckardt, Kai-Uwe .
AMERICAN JOURNAL OF PATHOLOGY, 2007, 170 (03) :830-842
[3]   Significance of postglomerular capillaries in the pathogenesis of chronic renal failure [J].
Bohle, A ;
MackensenHaen, S ;
Wehrmann, M .
KIDNEY & BLOOD PRESSURE RESEARCH, 1996, 19 (3-4) :191-195
[4]   Matricellular proteins: extracellular modulators of cell function [J].
Bornstein, P ;
Sage, EH .
CURRENT OPINION IN CELL BIOLOGY, 2002, 14 (05) :608-616
[5]   Homing to hypoxia: HIF-1 as a mediator of progenitor cell recruitment to injured tissue [J].
Ceradini, DJ ;
Gurtner, GC .
TRENDS IN CARDIOVASCULAR MEDICINE, 2005, 15 (02) :57-63
[6]   Hypoxia-responsive transcription factors [J].
Cummins, EP ;
Taylor, CT .
PFLUGERS ARCHIV-EUROPEAN JOURNAL OF PHYSIOLOGY, 2005, 450 (06) :363-371
[7]   Loss of the tumor suppressor Vhlh leads to upregulation of Cxcr4 and rapidly progressive glomerulonephritis in mice [J].
Ding, Mei ;
Cui, Shiying ;
Li, Chengjin ;
Jothy, Serge ;
Haase, Volker ;
Steer, Brent M. ;
Marsden, Philip A. ;
Pippin, Jeffrey ;
Shankland, Stuart ;
Rastaldi, Maria Pia ;
Cohen, Clemens D. ;
Kretzler, Matthias ;
Quaggin, Susan E. .
NATURE MEDICINE, 2006, 12 (09) :1081-1087
[8]  
Duffy MJ, 2003, THROMB HAEMOSTASIS, V89, P622
[9]   Progression in chronic kidney disease [J].
Eddy, AA .
ADVANCES IN CHRONIC KIDNEY DISEASE, 2005, 12 (04) :353-365
[10]   Impact of HIF-1α and HIF-2α on proliferation and migration of human pulmonary artery fibroblasts in hypoxia [J].
Eul, B ;
Rose, F ;
Krick, S ;
Savai, R ;
Goyal, P ;
Klepetko, W ;
Grimminger, F ;
Weissmann, N ;
Seeger, W ;
Hänze, J .
FASEB JOURNAL, 2005, 19 (13) :163-+