natriuretic-peptide--c-type and Reperfusion-Injury

Natriuretic peptides elicit vasodilation, increased sodium excretion and concomitant diuresis, and counteract the RAAS. In the heart itself, natriuretic peptides may also act anti-inflammatory and antifibrotic. This has led to the pursuit of natriuretic peptides and chemically modified peptides as adjunctive therapy in myocardial ischaemia. However, natriuretic peptide infusion may also influence the endogenous natriuretic peptide response and lipid accumulation. We hypothesised that a) natriuretic peptide infusion (BNP and CD-NP) is cardiomyocyte protective, b) affects the endogenous response, and c) facilitate cardiac lipid accumulation. We examined these effects in a minimally invasive porcine model of regional cardiac ischaemia and reperfusion. The studies were supplemented by a 48-hour porcine model of ischemia and reperfusion as well as an in vitro study of BNP administered in a HL-1 cell model of "ischaemia/reperfusion". Infarct size was determined by TTC staining, plasma troponin T release, and total RNA integrity in cardiac tissue samples. The endogenous response was assessed by a processing-independent proANP immunoassay and mRNA quantitation. Lipids in plasma and myocardial tissue were determined by TLC. The studies show that natriuretic peptides decrease cardiomyocyte damage, possibly partly through indirect mechanisms. Furthermore, BNP infusion completely inverts the endogenous response, whereas CD-NP infusion does not. Finally, both natriuretic peptides increase plasma free fatty acids, which is associated with an increased cardiac lipid accumulation in non-ischaemic myocardium. In conclusion, the studies suggest that natriuretic peptides are beneficial in terms of reduced cardiac injury. In addition, the endogenous natriuretic peptide response is inverted. The results advocate for pursuing natriuretic peptide treatment in ischaemia/reperfusion damage. However, the metabolic consequences in a cardiac tissue challenged by ischaemia should be pursued before testing the peptides in patients.

Topics: Animals; Blood Pressure; Caspase 1; Cholesterol; Cyclic GMP; Diuresis; Fatty Acids, Nonesterified; Female; Glycerol; Mice; Myocardial Infarction; Myocardial Ischemia; Myocytes, Cardiac; Natriuretic Peptide, Brain; Natriuretic Peptide, C-Type; Natriuretic Peptides; Reperfusion Injury; RNA, Messenger; Swine; Triglycerides; Troponin T; Tumor Cells, Cultured; Vascular Endothelial Growth Factor A

Although atrial natriuretic peptide has been shown to attenuate ischemia-reperfusion (IR)-induced kidney injury, the effect of natriuretic peptide receptor (NPR)-B activation on IR-induced acute kidney injury is not well documented. The purpose of the present study was to identify the effect of C-type natriuretic peptide (CNP), a selective activator of NPR-B, on the IR-induced acute kidney injury and its mechanisms involved.. Unilaterally nephrectomized rats were insulted by IR in their remnant kidney, and they were randomly divided into three groups: sham, vehicle+IR, and CNP+IR groups. CNP (0.2μg/kg/min) was administered intravenously at the start of a 45-min renal ischemia for 2h. Rats were then killed 24h after I/R, and the blood and tissue samples were collected to assess renal function, histology, TUNEL assay, and Western blot analysis of kidney Bax and Bcl-2 expressions.. The levels of blood urea nitrogen and serum creatinine were significantly increased in rats after IR compared with vehicle-treated rats. IR elevated apoptosis, Bcl-2/Bax ratio, TUNEL positivity, oxidative stress parameters, malondialdehyde concentration, and superoxide dismutase activity. IR also induced epithelial desquamation of the proximal tubules and glomerular shrinkage. CNP significantly attenuated the IR-induced increase in BUN and serum creatinine. Furthermore, CNP restored the suppressed renal cyclic guanosine 3' 5'-monophosphate levels caused by IR insult.. Study findings suggest that CNP could ameliorate IR-induced acute kidney injury through inhibition of apoptotic and oxidative stress pathways, possibly through NPR-B-cGMP signaling.

Topics: Acute Kidney Injury; Animals; Apoptosis; bcl-2-Associated X Protein; Blood Urea Nitrogen; Blotting, Western; Creatinine; Cyclic GMP; In Situ Nick-End Labeling; Male; Malondialdehyde; Natriuretic Peptide, C-Type; Oxidative Stress; Proto-Oncogene Proteins c-bcl-2; Rats; Rats, Wistar; Receptors, Atrial Natriuretic Factor; Reperfusion Injury; Signal Transduction; Superoxide Dismutase