Real-Time and Non-invasive Monitoring of the Activation of the IRE1α-XBP1 Pathway in Individuals with Hemodynamic Impairment

Abstract

Many stressors that are encountered upon kidney injury are likely to trigger endoplasmic reticulum (ER) stress, subsequently activating transcriptional, translational and metabolic reprogramming. Monitoring early cellular adaptive responses engaged after hemodynamic impairment yields may represent a clinically relevant approach. However, a non-invasive method for detecting the ER stress response has not been developed. We combined a metabolomic approach with genetic marker analyses using urine from individuals undergoing scheduled cardiac surgery under cardiopulmonary bypass to investigate the feasibility and significance of monitoring the ER stress response in the kidney. We developed an original method based on fragment analysis that measures urinary levels of the spliced X-box binding protein 1 (sXBP1) mRNA as a proxy of inositol-requiring enzyme 1α (IRE1α) activity because sXBP1 is absolutely sensitive and specific for ER stress. The early engagement of the ER stress response after ischemic stress is critical for protecting against tissue damage, and individuals who mount a robust adaptive response are protected against AKI. The clinical consequences of our findings are of considerable importance because ER stress is involved in numerous conditions that lead to AKI and chronic kidney disease; in addition, the detection of ER stress is straightforward and immediately available in routine practice.

A Weak Response to Endoplasmic Reticulum Stress Is Associated With Postoperative Organ Failure in Patients Undergoing Cardiac Surgery With Cardiopulmonary Bypass

“…In human, ERS is activated in the mononuclear cells of patients with septic acute lung injury, is involved in AKI and its expression is partly correlated with organ failure in patients with septic shock ( 10 , 14 , 16 ). A recent work has shown the feasibility of the non-invasive detection of the ERS in urine in patients undergoing cardiac surgery with CPB and indicates that an early and robust adaptive UPR is critical for endogenous protection to acute renal failure ( 17 ).…”

Endoplasmic reticulum stress and kidney dysfunction

“…In line with this, maintenance of the activity of the PERK pathway by salubrinal, which inhibits eIF2α dephosphorylation and reduces global protein translation, is protective against acute cyclosporine nephrotoxicity in rats [Pallet et al., ]. Finally, consistent with the protection afforded by the activity of the IRE1α‐sXBP1 pathway, individuals undergoing scheduled cardiac surgery under cardiopulmonary bypass who mount a robust adaptive response measured by the urinary levels of the spliced X‐box binding protein 1 (sXBP1) mRNA are protected against tissue damage and AKI [Fohlen et al., ].…”

“…high levels of sXBP1 mRNA) is critical for protection against AKI. Larger studies are required to determine the clinical significance of monitoring ER stress with urinary sXBP1 levels as a proxy and will delineate the range of medical conditions that can be monitored with this detection tool [Fohlen et al., ].…”

The cellular prion protein is a stress protein secreted by renal tubular cells and a urinary marker of kidney injury

“…To monitor PrP C in the setting of ischemia-reperfusion injury (IRI), we took advantage of the biocollection of a previous study 12 . From 17 February 2017 to 26 April 2017, 42 patients undergoing scheduled cardiac surgery with CPB were enrolled.…”

“…We then measured the concentrations of PrP C in urines of individuals with a kidney disease. To demonstrate the biological and clinical relevance of the detection of PrP C in urine, we monitored ER stress markers in urine of 19 patients undergoing scheduled cardiac surgery with cardiopulmonary bypass, which promote IRI in the kidney, a condition associated with ER stress (Supplementary Table 2) 12 . We repeatedly measured the urine angiogenin concentrations (an indirect marker of the activity of the IRE1α/sXBP1 axis 22 ), and NGAL, which is regulated by the PERK/ATF4 pathway 30 , to obtain information about the activation of the UPR during the CPB procedure.…”