Stress Signal Network between Hypoxia and ER Stress in Chronic Kidney Disease

Abstract

Chronic kidney disease (CKD) is characterized by an irreversible decrease in kidney function and induction of various metabolic dysfunctions. Accumulated findings reveal that chronic hypoxic stress and endoplasmic reticulum (ER) stress are involved in a range of pathogenic conditions, including the progression of CKD. Because of the presence of an arteriovenous oxygen shunt, the kidney is thought to be susceptible to hypoxia. Chronic kidney hypoxia is induced by a number of pathogenic conditions, including renal ischemia, reduced peritubular capillary, and tubulointerstitial fibrosis. The ER is an organelle which helps maintain the quality of proteins through the unfolded protein response (UPR) pathway, and ER dysfunction associated with maladaptive UPR activation is named ER stress. ER stress is reported to be related to some of the effects of pathogenesis in kidney, particularly in the podocyte slit diaphragm and tubulointerstitium. Furthermore, chronic hypoxia mediates ER stress in blood vessel endothelial cells and tubulointerstitium via several mechanisms, including oxidative stress, epigenetic alteration, lipid metabolism, and the AKT pathway. In summary, a growing consensus considers that these stresses interact via complicated stress signal networks, which leads to the exacerbation of CKD (Figure 1). This stress signal network might be a target for interventions aimed at ameliorating CKD.

Keywords: UPR signaling pathways; chronic kidney disease; er stress; hypoxia; stress signal network.

Figure 1

Putative stress signal network between ER stress and hypoxia in CKD. Abbreviations: Epo, erythropoietin; ER, endoplasmic reticulum CKD: chronic kidney disease; vLDL-R, very low lipoprotein receptor. Hypoxia and ER stress interact through a number of complicated pathways and lead to the exacerbation of CKD. The progression of CKD is caused via vascular damage, glomerular damage and tubulointerstitial injury. The mechanisms by which ER stress induces hypoxia include a change of oxygen demand in tissue, dysfunction of iron metabolism and reduction in EPO production. By contrast, chronic hypoxia induces ER stress through oxidative stress, epigenetic regulation by microRNA, overexpression of vLDL-R and the Akt pathway. These pathogenic factors could be targets for CKD therapy.