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

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 PrP C 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 PrP C elevation occurs in patients with chronic kidney disease. In addition, in patients undergoing cardiac surgery, detectable urine levels of PrP C significantly increase after cardiopulmonary bypass, a condition associated with activation of the IRE1-XBP1 pathway in the kidney. In conclusion, our study has identified PrP C as a novel urinary ER stress biomarker with potential utility in early diagnosis of ongoing acute or chronic kidney injury.

Anchorless risk or released benefit? An updated view on the ADAM10-mediated shedding of the prion protein

“…In recent years, protective functions have also been attributed to PrP in the kidney (Han et al 2020 ; Yoon et al 2021 ; Zhang et al 2015 ), and PrP is ‘secreted’ into the urine in response to chronic kidney disease and ER stress in kidney injury (Bignon et al 2020 ). However, before assessment of PrP in plasma can be used as a reliable biomarker, differentiation between sPrP and other PrP forms again seems appropriate.…”

Harnessing the Physiological Functions of Cellular Prion Protein in the Kidneys: Applications for Treating Renal Diseases

“…In the past, PrP C in kidney tissues has been only used as a proxy model for studying neuronal PrP C [ 66 ], which led to the current unavailability of literature dedicated towards examining the functions of PrP C in the kidneys. Given that recent studies on kidney injuries and PrP C have demonstrated that PrP C could be a reliable biomarker for renal injury [ 67 ] and protect cells against a chronic kidney disease (CKD) environment [ 68 ], further exploration of the link between various kidney diseases and endogenous PrP C is greatly merited. Throughout this review, we have summarized the current understandings of PrP C in the kidneys and its application in renal pathologies and identified potential PrP C -based therapeutic strategies for major kidney diseases, including acute and chronic kidney injury, renal fibrosis, and cancers.…”

“…Taken together, there seems to be sufficient evidence for PrP C -mediated protection against renal IR injury, particularly through modulation of the mitochondrial function and the ERK signaling pathway ( Figure 2 B). This provides a plausible explanation for why PrP C is secreted by renal epithelial cells under endoplasmic reticulum stress [ 67 ]. The current efforts to take advantage of such protective functions of PrP C will be reviewed in the following sections.…”

“…The kidneys play a critical role in maintaining the overall health of an individual by filtering toxic metabolic waste products [ 122 ] and maintaining adaptive tissue repair programs [ 67 , 143 ]. Compromised kidney functions often have multifactorial etiology [ 120 , 144 , 145 , 146 , 147 , 148 , 149 ], but they all progress towards chronic kidney disease (CKD), which is often diagnosed by a decreased glomerular filtration rate and persistently elevated levels of serum creatinine and albuminuria [ 143 ].…”