The endoplasmic reticulum stress and the unfolded protein response in kidney disease: Implications for vascular growth factors

Abstract

Acute kidney injury (AKI) and chronic kidney disease (CKD) represent an important challenge for healthcare providers. The identification of new biomarkers/pharmacological targets for kidney disease is required for the development of more effective therapies. Several studies have shown the importance of the endoplasmic reticulum (ER) stress in the pathophysiology of AKI and CKD. ER is a cellular organelle devolved to protein biosynthesis and maturation, and cellular detoxification processes which are activated in response to an insult. This review aimed to dissect the cellular response to ER stress which manifests with activation of the unfolded protein response (UPR) with its major branches, namely PERK, IRE1α, ATF6 and the interplay between ER and mitochondria in the pathophysiology of kidney disease. Further, we will discuss the relationship between mediators of renal injury (with specific focus on vascular growth factors) and ER stress and UPR in the pathophysiology of both AKI and CKD with the aim to propose potential new targets for treatment for kidney disease.

Keywords: Endoplasmic reticulum stress; acute kidney injury; chronic kidney disease; unfolded protein response; vascular growth factors.

FIGURE 1

ER stress drives different UPR‐mediated cellular/tissue outcomes in AKI and CKD. Acute and chronic insults to the kidney result in a transient or sustained activation of ER stress/mitochondria and UPR, respectively. ER stress/UPR plays an important role in determining favourable/not favourable clinical outcome of a disease

FIGURE 2

ER stress/UPR transient or sustained activation modulates tissue repair/injury and healthy/impaired vascular remodelling, respectively. A, Acute insults (AKI) stimulate a transient UPR that contributes to tissue repair. Conversely chronic insults, as seen in CKD, stimulate a sustained UPR which promotes tissue injury. B, In condition of ER stress, secondary to AKI or CKD, UPR plays a role in modulating the expression of vascular growth factors. The modulation of vascular growth factor expression drives a healthy or impaired vascular remodelling in condition of transient or sustained UPR activation, respectively

FIGURE 3

VEGFA/VEGFR2 system differentially modulates the UPR activation in condition of transient or sustained ER stress. A, In physiology, UPR is activated by the VEGF/VEGFR2 system in the absence of ER stress. The VEGF/VEGFR2 system activates both PERK and ATF6 resulting in cell survival and inhibition of the pro‐apoptotic pathway CHOP favouring a cells’ survival. B, AKI mediates (transient) ER stress and PERK and ATF6 activation, which, in turn, drive an up‐regulation of VEGFA. VEGFA, with an autocrine/paracrine mechanism, activates PERK and ATF6 via VEGFR2 activation. The balance between VEGFA/VEGFR2 system and transient UPR‐mediated PERK and ATF6 activation results in lack of stimulation of CHOP‐mediated cell apoptosis, cell survival and tissue repair. C, CKD after AKI or CKD is characterized by sustained ER stress and UPR stimulation. Sustained ER stress‐mediated UPR activation results in CHOP‐mediated cell apoptosis. The sustained stimulation of PERK up‐regulates the VEGFA/VEGFR2 system resulting in a synergistic (VEGFA/UPR) activation of CHOP and cell apoptosis resulting in tissue injury