Prion Protein Protects against Renal Ischemia/Reperfusion Injury

Abstract

The cellular prion protein (PrPC), a protein most noted for its link to prion diseases, has been found to play a protective role in ischemic brain injury. To investigate the role of PrPC in the kidney, an organ highly prone to ischemia/reperfusion (IR) injury, we examined wild-type (WT) and PrPC knockout (KO) mice that were subjected to 30-min of renal ischemia followed by 1, 2, or 3 days of reperfusion. Renal dysfunction and structural damage was more severe in KO than in WT mice. While PrP was undetectable in KO kidneys, Western blotting revealed an increase in PrP in IR-injured WT kidneys compared to sham-treated kidneys. Compared to WT, KO kidneys exhibited increases in oxidative stress markers heme oxygenase-1, nitrotyrosine, and Nε-(carboxymethyl)lysine, and decreases in mitochondrial complexes I and III. Notably, phosphorylated extracellular signal-regulated kinase (pERK) staining was predominantly observed in tubular cells from KO mice following 2 days of reperfusion, a time at which significant differences in renal dysfunction, histological changes, oxidative stress, and mitochondrial complexes between WT and KO mice were observed. Our study provides the first evidence that PrPC may play a protective role in renal IR injury, likely through its effects on mitochondria and ERK signaling pathways.

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

“…PrP C is expressed at the apical cell surface of polarized proximal tubule cells and promotes kidney iron uptake 39 . Interestingly, PrP C is upregulated in the kidney following IRI 40 , in line with our own data in CBP patients, and the results indicate that PrP C -knockout animals have an increase sensibility to IRI. However, the authors did not assess the link with the UPR nor the levels of urinary PrP C following IRI.…”

Show Me Your Friends and I Tell You Who You Are: The Many Facets of Prion Protein in Stroke

“…In that study, protection conferred by PrPC overexpression resulted in reduced ROS-related cell damage [ 55 ]. A similar situation was observed in the kidney, where PrP0/0 mice showed more tubular damage and increased cell death related to ROS than WT [ 56 ]. The reported upregulation of PrPC in gastric cancer cell lines may also protect them from hypoxia [ 57 ].…”

Tauroursodeoxycholic acid reduces ER stress by regulating of Akt-dependent cellular prion protein

“…Blood flow ratio, limb salvage, expression levels of MnSOD, transplanted cell survival, and vessel repair were all increased following transplantation of TUDCA-treated MSCs and were mediated by PrP C expression. PrP C knockout mice showed severe renal dysfunction and structural damage following renal ischemia/reperfusion injury40. Our results indicate that TUDCA-treated MSCs have enhanced bioactivities, and that transplantation of TUDCA-treated MSCs could be used in stem cell-based therapeutics for ischemic diseases.…”