Nitric oxide bioavailability and antioxidant defence as therapeutic targets in synergistic model of acute kidney injury and hypertension

Abstract

Hipertenzija, koja se izmedu ostalog karakteriše i deficitom vasodilatatornog azotnog monoksida (AM), mačajno pogoršava kliničku sliku postishernične akutne bubrežne slabosti (ABS) kod ljudi. Ponovno vraćanje krvi u bubrežno tkivo, samo po sebi dovodi do masovne produkcije slobodnih vrsta kiseonika (SVK) i pogoršanja ishemijske povrede. Ispitivali smo potencijalni zaštitni efekat primene donora AM-a, kao i uklanjanja SVK na sistemske i bubrežne hemodinamske parametre, kao i na strukturu i funkciju bubrega pacova sa urodenom hipertenzijom (PUH), kojima je izazivana postishemična ABS. Za navedene potrebe, PUH su dobijali donor AM, L-arginin, prirodni sakupljač SRK vitamin C (Vit C) ili sintetski mimetik enzima superoksid dismutase TEMPOL, tokom ishemije-reperfuzije bubrega u trajanju od 40 minuta. Tretman L-argininom je poboljšao sistemsku i bubreżnu hemodinarniku, ali nije uspeo da smanji ośtećenje bubrega. Nasuprot tome, intenzitet nekroze i dilatacije tubula su bili mačajno smanjeni kod pacova u ABS+Vit C grupi u poredenju sa kontrolnom ABS grupom. Uprkos smanjenju lipidne peroksidacije u plazmi, kao i renalnog vaskularnog otpora, tretman TEMPOL-om nije uspeo da ublaži reperfuzijom nastala oštećenja bubreżnog tkiva kod PUH. Naši rezultati ukazuju na to da SVK učestvuju u reperfuzionim oštećenjima bubrega, a da su sintetski mimetik superoksid dismutaze i donor AM neefikasni u zaštiti glomerula i tubula nakon nastanka ABS kod PUH. Sa druge strane, naši rezultati sugerišu daje Vit C, prirodni antioksidant, hemoprotektant umerenog zaśtitnog dejstva protiv ishemijsko-reperfuzionih povreda bubrega u hipertenzivnim okolnostima. Ova zaštita je većinski povezana sa direktnim uklanjanjem SVK.

Hypertension, which is among others characterized by reducing of nitric oxide (NO) mediated vasodilatation, strongly aggravates postischemic acute kidney injury (AKI) in humans. Kidney reperfusion itself increases ischemic injury through the massive production of oxygen-free radicals. We investigated protective potential of NO supplementation and superoxide radical scavenging on systemic and renal haemodynamic parameters as well as kidney function and structure in spontaneously hypertensive rats (SHR) with induced postischemic AKI. For these purposes, SHR were subjected to NO donor L-arginine, natural oxidant scavenger vitamin C (Vit C) or synthetic superoxide dismutase mimetic TEMPOL during 40 minutes kidney ischaemia-reperfusion period. L-arginine supplementation improves systemic and renal hemodynamic but failed to reduce kidney tubular injuries. In opposite, intensity of tubular necrosis and dilatation was markedly reduced in AKI+Vit C group in comparison to AKI control. Despite blunting of lipid peroxidation in plasma and diminishing of renal vascular resistance, TEMPOL treatment also failed to reduce kidney tissue injuries induced by reperfusion in SHR. Our results suggest that superoxide radicals participate in kidney reperfusion injuries while synthetic superoxide dismutase and NO supplementation are ineffective in glomerular and tubular protection after AKI episode in hypertensive rats. On the other hand, our results promote natural antioxidant, vitamin C, as a moderately effective chemoprotectant against kidney ischemia-reperfusion injuries in hypertensive surrounding. Protection is mainly related to the direct superoxide radical scavenging.