Renal Ischemia/Reperfusion Early Induces Myostatin and PCSK9 Expression in Rat Kidneys and HK-2 Cells

被引:10
|
作者
Barisione, Chiara [1 ]
Verzola, Daniela [2 ,3 ]
Garibaldi, Silvano [2 ]
Ferrari, Pier Francesco [1 ]
Garibotto, Giacomo [2 ,3 ]
Ameri, Pietro [2 ,4 ]
Pane, Bianca [1 ,5 ,6 ]
Spinella, Giovanni [1 ,5 ,6 ]
Pratesi, Giovanni [1 ,5 ]
Palombo, Domenico [1 ,5 ,6 ]
机构
[1] Univ Genoa, Dept Surg & Integrated Diagnost Sci, Viale Benedetto XV 6, I-16132 Genoa, Italy
[2] Univ Genoa, Dept Internal Med, Viale Benedetto XV 6, I-16132 Genoa, Italy
[3] IRCCS Osped Polidin San Martino, Div Nephrol v, Largo Rosanna Benzi 10, I-16132 Genoa, Italy
[4] Cardiovasc Dis Unit, IRCCS Osped Policlin San Martino, Largo Rosanna Benzi 10, I-16132 Genoa, Italy
[5] IRCCS Osped Policlin San Martino, Vasc & Endovasc Surg Unit, Largo Rosanna Benzi 10, I-16132 Genoa, Italy
[6] Univ Genoa, Res Ctr Biol Inspired Engn Vasc Med & Longev, Via Montallegro 1, I-16145 Genoa, Italy
关键词
oxidative stress; mitochondrial dysfunction; renal injury; aorta cross-clamping; tubular necrosis; ISCHEMIA-REPERFUSION INJURY; VISCERAL ISCHEMIA; AORTIC-ANEURYSMS; SKELETAL-MUSCLE; DAMAGE; MITOCHONDRIA; MODULATION; REPAIR;
D O I
10.3390/ijms22189884
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
During visceral interventions, the transient clampage of supraceliac aorta causes ischemia/reperfusion (I/R) in kidneys, sometime resulting in acute renal failure; preclinical studies identified redox imbalance as the main driver of I/R injury. However, in humans, the metabolic/inflammatory responses seem to prevail on oxidative stress. We investigated myostatin (Mstn) and proprotein convertase subtilisin/kexin type 9 (PCSK9), proatherogenic mediators, during renal I/R. Compared to sham-operated animals, the kidneys of rats who had experienced ischemia (30 min) had higher Mstn and PCSK9 expression after 4 h of reperfusion. After 24 h, they displayed tubular necrosis, increased nitrotyrosine positivity, and nuclear peroxisome proliferator-activated receptor gamma coactivator-1alpha relocation, markers of oxidative stress and mitochondria imbalance. Mstn immunopositivity was increased in tubuli, while PCSK9 immunosignal was depleted; systemically, PCSK9 was higher in plasma from I/R rats. In HK-2 cells, both ischemia and reperfusion enhanced reactive oxygen species production and mitochondrial dysfunction. H2O2 upregulated Mstn and PCSK9 mRNA after 1 and 3.5 h, respectively. Accordingly, ischemia early induced Mstn and PCSK9 mRNA; during reperfusion Mstn was augmented and PCSK9 decreased. Mstn treatment early increased PCSK9 expression (within 8 h), to diminish over time; finally, Mstn silencing restrained ischemia-induced PCSK9. Our study demonstrates that renal I/R enhances Mstn and PCSK9 expression and that Mstn induces PCSK9, suggesting them as therapeutic targets for vascular protection during visceral surgery.
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页数:21
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