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Prion Protein Protects against Renal Ischemia/Reperfusion Injury.

Zhang B, Cowden D, Zhang F, Yuan J, Siedlak S, Abouelsaad M, Zeng L, Zhou X, O'Toole J, Das AS, Kofskey D, Warren M, Bian Z, Cui Y, Tan T, Kresak A, Wyza RE, Petersen RB, Wang GX, Kong Q, Wang X, Sedor J, Zhu X, Zhu H, Zou WQ - PLoS ONE (2015)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, HuBei, The People's Republic of China; Department of Surgery, Davis Heart and Lung Research Institute, The Ohio State University, Columbus, Ohio, United States of America; Key Laboratory of Ministry of Health and Key Laboratory of Ministry of Education, Wuhan, HuBei, The People's Republic of China.

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.

No MeSH data available.


Related in: MedlinePlus

Histological changes and TUNEL apoptosis assays of sham and IR-injured WT and KO mice.(A) Hematoxylin and eosin (H&E) staining images are representative renal tissue sections from three mice of each group including WT and KO control (CTL) and IR-injured on day 2 (bar = 50 μm; original magnification, x 400). Black arrows indicate dilated tubules and brush-border damage. Red arrows indicate tubular vacuolization. Blue arrows indicate peritubular capillary congestion. Orange arrow indicates cast formation. Green arrows indicate necrotic changes, such as the frequent presence of pyknotic nuclei. (B) TUNEL apoptosis images are representative renal tissue sections from three mice of each group including WT and KO control (CTL) and IR-injured on day 2 (bar = 50 μm; original magnification, x 400). Black arrows indicate apoptotic cells with brown staining. (C) Quantitative analysis of apoptotic cells on day 0, 1, 2, and 3. Apoptotic cells were quantified by counting TUNEL-positive cells in 4 random high-power fields (HPFs, x 400). *p < 0.05.
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pone.0136923.g002: Histological changes and TUNEL apoptosis assays of sham and IR-injured WT and KO mice.(A) Hematoxylin and eosin (H&E) staining images are representative renal tissue sections from three mice of each group including WT and KO control (CTL) and IR-injured on day 2 (bar = 50 μm; original magnification, x 400). Black arrows indicate dilated tubules and brush-border damage. Red arrows indicate tubular vacuolization. Blue arrows indicate peritubular capillary congestion. Orange arrow indicates cast formation. Green arrows indicate necrotic changes, such as the frequent presence of pyknotic nuclei. (B) TUNEL apoptosis images are representative renal tissue sections from three mice of each group including WT and KO control (CTL) and IR-injured on day 2 (bar = 50 μm; original magnification, x 400). Black arrows indicate apoptotic cells with brown staining. (C) Quantitative analysis of apoptotic cells on day 0, 1, 2, and 3. Apoptotic cells were quantified by counting TUNEL-positive cells in 4 random high-power fields (HPFs, x 400). *p < 0.05.

Mentions: To determine whether renal dysfunction induced by IR injury was associated with renal pathologic damage, hematoxylin & eosin (H&E) staining of the kidney was performed. Both WT and KO mice displayed tubular damage on days 1, 2, and 3 after renal IR injury, as evidenced by tubular dilatation/vacuolation, loss of the brush border, cast formation, tubular necrosis, and peritubular capillary congestion at the site of the renal cortex or corticomedullary junction (Fig 2A). Consistent with the renal dysfunction described above, more significant pathological changes were observed in KO than in WT kidneys, especially on day 2. The renal medulla in kidneys from sham KO and WT was largely unaffected (Fig 2A).


Prion Protein Protects against Renal Ischemia/Reperfusion Injury.

Zhang B, Cowden D, Zhang F, Yuan J, Siedlak S, Abouelsaad M, Zeng L, Zhou X, O'Toole J, Das AS, Kofskey D, Warren M, Bian Z, Cui Y, Tan T, Kresak A, Wyza RE, Petersen RB, Wang GX, Kong Q, Wang X, Sedor J, Zhu X, Zhu H, Zou WQ - PLoS ONE (2015)

Histological changes and TUNEL apoptosis assays of sham and IR-injured WT and KO mice.(A) Hematoxylin and eosin (H&E) staining images are representative renal tissue sections from three mice of each group including WT and KO control (CTL) and IR-injured on day 2 (bar = 50 μm; original magnification, x 400). Black arrows indicate dilated tubules and brush-border damage. Red arrows indicate tubular vacuolization. Blue arrows indicate peritubular capillary congestion. Orange arrow indicates cast formation. Green arrows indicate necrotic changes, such as the frequent presence of pyknotic nuclei. (B) TUNEL apoptosis images are representative renal tissue sections from three mice of each group including WT and KO control (CTL) and IR-injured on day 2 (bar = 50 μm; original magnification, x 400). Black arrows indicate apoptotic cells with brown staining. (C) Quantitative analysis of apoptotic cells on day 0, 1, 2, and 3. Apoptotic cells were quantified by counting TUNEL-positive cells in 4 random high-power fields (HPFs, x 400). *p < 0.05.
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pone.0136923.g002: Histological changes and TUNEL apoptosis assays of sham and IR-injured WT and KO mice.(A) Hematoxylin and eosin (H&E) staining images are representative renal tissue sections from three mice of each group including WT and KO control (CTL) and IR-injured on day 2 (bar = 50 μm; original magnification, x 400). Black arrows indicate dilated tubules and brush-border damage. Red arrows indicate tubular vacuolization. Blue arrows indicate peritubular capillary congestion. Orange arrow indicates cast formation. Green arrows indicate necrotic changes, such as the frequent presence of pyknotic nuclei. (B) TUNEL apoptosis images are representative renal tissue sections from three mice of each group including WT and KO control (CTL) and IR-injured on day 2 (bar = 50 μm; original magnification, x 400). Black arrows indicate apoptotic cells with brown staining. (C) Quantitative analysis of apoptotic cells on day 0, 1, 2, and 3. Apoptotic cells were quantified by counting TUNEL-positive cells in 4 random high-power fields (HPFs, x 400). *p < 0.05.
Mentions: To determine whether renal dysfunction induced by IR injury was associated with renal pathologic damage, hematoxylin & eosin (H&E) staining of the kidney was performed. Both WT and KO mice displayed tubular damage on days 1, 2, and 3 after renal IR injury, as evidenced by tubular dilatation/vacuolation, loss of the brush border, cast formation, tubular necrosis, and peritubular capillary congestion at the site of the renal cortex or corticomedullary junction (Fig 2A). Consistent with the renal dysfunction described above, more significant pathological changes were observed in KO than in WT kidneys, especially on day 2. The renal medulla in kidneys from sham KO and WT was largely unaffected (Fig 2A).

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, HuBei, The People's Republic of China; Department of Surgery, Davis Heart and Lung Research Institute, The Ohio State University, Columbus, Ohio, United States of America; Key Laboratory of Ministry of Health and Key Laboratory of Ministry of Education, Wuhan, HuBei, The People's Republic of China.

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.

No MeSH data available.


Related in: MedlinePlus