Abstract
Endoplasmic Reticulum (ER) stress underlies the pathogenesis of numerous kidney diseases. A better care of patients with kidney disease involves the identification and validation of ER stress biomarkers in the early stages of kidney disease. For the first time to our knowledge, we demonstrate that the prion protein PrPC is secreted in a conventional manner by ER-stressed renal epithelial cell under the control of the transcription factor x-box binding protein 1 (XBP1) and can serve as a sensitive urinary biomarker for detecting tubular ER stress. Urinary PrPC elevation occurs in patients with chronic kidney disease. In addition, in patients undergoing cardiac surgery, detectable urine levels of PrPC significantly increase after cardiopulmonary bypass, a condition associated with activation of the IRE1-XBP1 pathway in the kidney. In conclusion, our study has identified PrPC as a novel urinary ER stress biomarker with potential utility in early diagnosis of ongoing acute or chronic kidney injury.
Highlights
Kidneys have to cope with a wide array of injuries that translate into elementary stressors at the cellular level
To assess whether the PrPC-encoding PRNP transcripts are sensitive to Endoplasmic Reticulum (ER) stressors in human renal epithelium, we monitored PRNP mRNA expression during a 24-h kinetics of exposure of Human Renal Epithelial Cells (HREC) to 250 nM Thapsigargin (Tg) or 250 ng/ml Tunicamycin (Tun)
Robust inductions of unfolded protein response (UPR) transcripts and PRNP mRNA were found in primary HREC exposed for 24 h to Tg, Tun or BFA (Supplementary Fig. 1A)
Summary
Kidneys have to cope with a wide array of injuries that translate into elementary stressors at the cellular level. Adaptive responses to these stresses are molecular systems that primarily aim to eradicate or reduce stress intensity and promote metabolic reprograming to maintain cellular homeostasis and other vital functions[1]. Adaptive stress responses shape the endogenous repair and scarring equilibrium in tissues. As such, they are critical for tissue remodeling, and can impact the functional outcomes of the injured kidney, leading to chronic kidney disease (CKD)[2,3]. Genes that are regulated by sXBP1 enhance protein folding, transport, and Official journal of the Cell Death Differentiation Association
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