Ischemic preconditioning reduces endoplasmic reticulum stress and upregulates hypoxia inducible factor-1α in ischemic kidney: the role of nitric oxide

Abstract

BackgroundAlthough recent studies indicate that renal ischemic preconditioning (IPC) protects the kidney from ischemia-reperfusion (I/R) injury, the precise protective mechanism remains unclear. In the current study, we investigated whether early IPC could upregulate hypoxia inducible transcription factor-1α (HIF-1α) expression and could reduce endoplasmic reticulum (ER) stress after renal I/R and whether pharmacological inhibition of nitric oxide (NO) production would abolish these protective effects.MethodsKidneys of Wistar rats were subjected to 60 min of warm ischemia followed by 120 min of reperfusion (I/R group), or to 2 preceding cycles of 5 min ischemia and 5 min reperfusion (IPC group), or to intravenously injection of NG-nitro-L-arginine methylester (L-NAME, 5 mg/kg) 5 min before IPC (L-NAME+IPC group). The results of these experimental groups were compared to those of a sham-operated group. Sodium reabsorption rate, creatinine clearance, plasma lactate dehydrogenase (LDH) activity, tissues concentrations of malonedialdehyde (MDA), HIF-1α and nitrite/nitrate were determined. In addition, Western blot analyses were performed to identify the amounts of Akt, endothelial nitric oxide synthase (eNOS) and ER stress parameters.ResultsIPC decreased cytolysis, lipid peroxidation and improved renal function. Parallely, IPC enhanced Akt phosphorylation, eNOS, nitrite/nitrate and HIF-1α levels as compared to I/R group. Moreover, our results showed that IPC increased the relative amounts of glucose-regulated protein 78 (GRP78) and decreased those of RNA activated protein kinase (PKR)-like ER kinase (PERK), activating transcription factor 4 (ATF4) and TNF-receptor-associated factor 2 (TRAF2) as judged to I/R group. However, pre treatment with L-NAME abolished these beneficial effects of IPC against renal I/R insults.ConclusionThese findings suggest that early IPC protects kidney against renal I/R injury via reducing oxidative and ER stresses. These effects are associated with phosphorylation of Akt, eNOS activation and NO production contributing thus to HIF-1α stabilization. The beneficial impact of IPC was abolished when NO production is inhibited before IPC application.

Hypoxia: The Force that Drives Chronic Kidney Disease

“…[287][288][289][290][291] Tissue damage effected by these species is augmented by intermittent hypoxia reducing renal expression of antioxidants. 292 In addition, intermittent hypoxia induces the sympathetic nervous system to increase vascular resistance, downregulates expression of the kallikrein-kallistatin vasodilator Shelley Transforming growth factor β inhibition 446 Pro-fibrotic metalloproteinase inhibition 447 Anti-fibrotic metalloproteinase activation 447 Destabilization of renal Remote ischemic pre-conditioning [384][385][386][387][388][389][390] hypoxia-inducible factor Prolyl hydroxylase inhibition 244,448 von Hippel-Lindau protein inhibition 449 pathway, and activates the renal renin-angiotensin-aldosterone system to cause vasoconstriction. [293][294][295][296][297][298][299] Together these processes conspire to produce renal fibrosis and sustained hypertension and their associated means of reducing renal oxygenation ( figure 1).…”

“…This procedure stabilizes HIF-1α in the kidney, thereby conferring protection against a subsequent period of prolonged hypoxia. 385 Pre-conditioning by having cobalt chloride in drinking water or by breathing xenon, carbon monoxide, or isoflurane gas also stabilizes HIF-1α and confers renoprotection. [386][387][388][389][390] The clear limitation of ischemic preconditioning is that it can only be deployed against a defined episode of acute hypoxia known to be imminent, such as occurs after artery clamping in transplant surgery, or the injection of radiocontrast medium.…”

Effects of trimetazidine on the Akt/eNOS signaling pathway and oxidative stress in anin vivorat model of renal ischemia-reperfusion

“…It was reported that NO plays a crucial role in defending ischemic kidneys against I/R injury. 16 Besides, Cau et al 13 reported that HIF-1a accumulation protects the kidney against acute ischemic injury. The present study was undertaken to investigate whether the renoprotective mechanisms of TMZ implicated the Akt/eNOS/HIF-1a signaling pathway to reduce oxidative stress following warm renal I/R injury in rats.…”

Endoplasmic reticulum stress and its effects on renal tubular cells apoptosis in ischemic acute kidney injury

“…The beneficial impact of early ischemic PC was dependent on nitric oxide (NO) levels, as the protective effect was abolished when NO production was inhibited before early ischemic PC application. 44 The early protective effects on ER stress could possibly be because ischemic PC leads to a pro-survival phenotype in different cells. In renal epithelial cells suffering from oxidative injury, preconditioning with ER stress caused activation of ERK1/2 signaling, accompanied by a reduction in JNK activation.…”