Abstract
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.
Highlights
4 h of reflow, changes in Mstn and proprotein convertase subtilisin/kexin type 9 (PCSK9): mRNA levels were not significantly affected, with a tendency to Mstn lowering mRNA (Figure 1A), protein expression was augmented for both Mstn and PCSK9 (p < 0.01 and p < 0.05, respectively), as detected by western blot analysis (Figure 1B)
Periodic acid-Schiff (PAS) histological staining revealed a patch-like distribution of viable and damaged tubular cells; necrotic cells were swollen, with unevenly stained cytoplasm, and some of them were sloughed into the tubuli lumen (Figure 2A)
We investigated the role of myostatin (Mstn) and proprotein convertase subtilisin/kexin type 9 (PCSK9), mediators involved in the dysregulation of metabolism and catabolic/inflammatory disorders, so far unexplored in the context of renal I/R
Summary
Visceral vascular surgery often requires aortic cross-clamping proximally to the celiac artery, causing rapid hemodynamic changes in the downstream organs: the sudden decrease of the blood flow and the acute hypoxic moiety drive the shift from aerobic to anaerobic metabolism, the development of acidosis, and the increased cell membrane conditions of the Creative Commons. Permeability; tissue reperfusion after clamp removal leads to the activation of prooxidant, inflammatory pathways, and cellular damage. This sequence of events causes the so-called ischemia/reperfusion (I/R) injury in kidneys, liver, bowel, spinal cord, and inferior limbs. The overproduced superoxide anion radical (O2 − ) may react with nitric oxide to form peroxynitrite, followed by the nitration of proteins, the oxidation of thiols, or decomposition into hydroxyl radical ( OH)
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