The Role of Protein Kinase C Epsilon in the Regulation of Endothelial Nitric Oxide Synthase (eNOS) During Oxidative Stress Caused by Extracorporeal Shock Wave Lithotripsy (ESWL)

摘要

ESWL is an effective, non-invasive therapy utilized to fragment stones in the kidney and urinary tract. A lithotripter generates high-energy acoustic pulses and propagates those shock waves through a lens towards focal point at the location of the stone. After treatment, fragmentation of the stone allows debris to be cleared by flow of the urinary tract. Although lithotripsy provides a safer alternative to invasive treatments, ESWL may cause prolonged vasoconstriction after ESWL treatment, reducing renal blood flow and resulting in subsequent endothelial dysfunction, which may cause kidney damage leading to acute to chronic hypertension clinically [1]. ESWL-induced vascular oxidative stress and further endothelial dysfunction may be mediated by reduced levels of endothelial-derived nitric oxide (NO) and/or increased reactive oxygen species. Previously we have shown that ESWL increases hydrogen peroxide (H2O2) release and decreases NO release, resulting in decreased NO bioavailability and increased oxidative stress [2]. When the dihydrobiopterin to tetrahydrobiopterin ratio is increased, eNOS becomes uncoupled and produces superoxide (SO) instead of NO [3]. SO is converted to H2O2 by superoxide dismutase. Protein kinase C epsilon (PKC-ε) positively regulates eNOS activity by phosphorylation at Ser-1177 and is expressed in endothelial cells, but not in leukocytes. Previously it was shown that cell-permeable myristoylated (Myr) PKC-ε activator (PKC-ε+) and inhibitor (PKC-ε-) peptides dose-dependently increased and decreased NO release, respectively, in aortic tissue [4]. By using PKC-ε activator and inhibitor peptides, we can determine the role of PKC-e in ESWL-induced oxidative stress through regulating eNOS.