Hypoxia: The Force that Drives Chronic Kidney Disease

Abstract

In the United States the prevalence of end-stage renal disease (ESRD) reached epidemic proportions in 2012 with over 600,000 patients being treated. The rates of ESRD among the elderly are disproportionally high. Consequently, as life expectancy increases and the baby-boom generation reaches retirement age, the already heavy burden imposed by ESRD on the US health care system is set to increase dramatically. ESRD represents the terminal stage of chronic kidney disease (CKD). A large body of evidence indicating that CKD is driven by renal tissue hypoxia has led to the development of therapeutic strategies that increase kidney oxygenation and the contention that chronic hypoxia is the final common pathway to end-stage renal failure. Numerous studies have demonstrated that one of the most potent means by which hypoxic conditions within the kidney produce CKD is by inducing a sustained inflammatory attack by infiltrating leukocytes. Indispensable to this attack is the acquisition by leukocytes of an adhesive phenotype. It was thought that this process resulted exclusively from leukocytes responding to cytokines released from ischemic renal endothelium. However, recently it has been demonstrated that leukocytes also become activated independent of the hypoxic response of endothelial cells. It was found that this endothelium-independent mechanism involves leukocytes directly sensing hypoxia and responding by transcriptional induction of the genes that encode the β2-integrin family of adhesion molecules. This induction likely maintains the long-term inflammation by which hypoxia drives the pathogenesis of CKD. Consequently, targeting these transcriptional mechanisms would appear to represent a promising new therapeutic strategy.

Keywords: CD43; CD45; Gene transcription; Hypoxia; Kidney disease; Leukocyte adhesion; β2-integrins.

Figure 1

The hypoxia cycle driving chronic kidney disease. A constellation of environmental, behavioral, and physiologic risk factors reduce systemic oxygenation. In many cases these conditions exacerbate one another. Due to its vascular architecture and physiologic function, the kidney is particularly vulnerable to lowered oxygen tensions. This vulnerability is counteracted by defense mechanisms centered around activation of hypoxia-inducible factor. While these defense mechanisms are effective when periods of hypoxia are brief, they are overwhelmed when risk factors cause prolonged hypoxia. Under these circumstances a range of pathological cellular processes are activated, all of which aggravate renal hypoxia by metabolically consuming oxygen (red arrows). In addition, these processes cause renal fibrosis and vasoconstriction further aggravating hypoxia by limiting oxygen diffusion and reducing erythrocyte access (orange arrows). The net result is that a self-reinforcing cycle is established in which hypoxia causes cellular pathologies that themselves compromise renal oxygenation. The inevitable consequence of this cycle is progressive chronic kidney disease.

Figure 2

Recruitment of inflammatory leukocytes into renal tissue. When leukocytes (orange spheres) are non-activated they are maintained in the circulation by repulsive forces conferred by CD43 and CD45 (blue ellipsoids) expressed on their surface. Leukocytes are activated by hypoxia either directly or indirectly as a result of responding to chemokines and cytokines released from hypoxic kidney tissue. The initial consequence of this activation is that the expression of anti-adhesive CD43 and CD45 is reduced allowing leukocytes to engage in fast-rolling along arterial cell walls (pink octahedrons) tethered by endothelial selectins (purple ellipsoids) binding leukocyte carbohydrate moieties. Fast-rolling is first slowed and then halted by β2-integrins (red ellipsoids) being induced on the leukocyte surface and binding endothelial extracellular matrix and intercellular adhesion molecules (ICAM-EXMX) (speckled purple ellipsoids). The β2-integrins subsequently mediate extravasation and chemotaxis through the traction they impart at the leukocyte leading-surface. Once embedded within renal tissue activated leukocytes drive fibrosis through phagocytosis, self-inflicted apoptosis and the release of cytokines and chemokines (orange arrowed-crosses) that induce the activation or apoptosis of surrounding cells and recruit additional inflammatory cells from the circulation. The vast majority of infiltrating inflammatory leukocytes eventually undergo apoptosis. However, a small proportion can remain resident with reduced β2-integrin expression and “memory” that allows rapid re-activation.