PKA-mediated eNOS phosphorylation in the protection of ischemic preconditioning against no-reflow

Li, Xiangdong; Cheng, Yuntao; Yuejin, Yang; Meng, Xia; Zhao, Jinglin; Zhang, Haitao; Wu, Yongjian; Shang, You; Wu, Yiling

doi:10.1016/j.mvr.2012.04.002

Cited by 36 publications

(29 citation statements)

References 48 publications

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“…Akt, which is activated by phosphorylation via activated PI3K, phosphorylates eNOS on serine 1177 (p-eNOS), thereby activating this enzyme [38,39]. The protective effect of this signaling pathway, PI3K/Akt/eNOS, has been confirmed in many studies [15,40], including LIPC [41,42]. In this study, we validated the activation of this signaling pathway, and also demonstrated its role in regulating renal microcirculation.…”

Section: Discussionsupporting

confidence: 61%

Limb ischemic preconditioning ameliorates renal microcirculation through activation of PI3K/Akt/eNOS signaling pathway after acute kidney injury

et al. 2020

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Purpose: Contrast-induced acute kidney injury (CI-AKI) resulting from administration of iodinated contrast media (CM) is the third leading cause of hospital-acquired acute kidney injury and is associated with substantial morbidity and mortality. Deteriorated renal microcirculation plays an important role in CI-AKI. Limb ischemic preconditioning (LIPC), where brief and non-injurious ischemia/reperfusion is applied to a limb prior to the administration of the contrast agent, is emerging as a promising strategy for CI-AKI prevention. However, it is not known whether the renal protection of LIPC against CI-AKI is mediated by regulation of renal microcirculation and the molecular mechanisms remain largely unknown. Methods: In this study, we examined the renal cortical and medullary blood flow in a stable CI-AKI model using 5/6-nephrectomized (NE) rat. The LIPC and sham procedures were performed prior to the injection of CM. Furthermore, we analyzed renal medulla hypoxia using in vivo labeling of hypoxyprobe. Pharmacological inhibitions and western blotting were used to determine the underlying molecular mechanisms. Results: In this study, we found LIPC significantly ameliorated CM-induced reduction of medullary blood flow and attenuated CM-induced hypoxia. PI3K inhibitor (wortmannin) treatment blocked the regulation of medullary blood flow and the attenuation of hypoxia of LIPC. Phosphorylation of Akt/eNOS was significantly decreased via wortmannin treatment compared with LIPC. Nitric oxide synthase-inhibitor [Nω-nitro-l-arginine methyl ester (L-NAME)] treatment abolished the above effects and decreased phosphorylation of eNOS, but not Akt. Conclusions: Collectively, the results demonstrate that LIPC ameliorates CM-induced renal vasocontraction and is mediated by activation of PI3K/Akt/eNOS signaling pathway.

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Section: Discussionsupporting

confidence: 61%

Limb ischemic preconditioning ameliorates renal microcirculation through activation of PI3K/Akt/eNOS signaling pathway after acute kidney injury

et al. 2020

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“…This by itself could lead to a protection at reperfusion as increased eNOS phosphorylation on activating residues has been involved in the protective effect of cardiac ischemic preconditioning (38,39). In this work, eNOS phosphorylation occurred specifically during MP and our data suggest that this is an AMPKa-dependent (MP specifically activated AMPKa but not Akt or PKA compared to CS).…”

Section: Discussionmentioning

confidence: 47%

Mechanistic Analysis of Nonoxygenated Hypothermic Machine Perfusion’s Protection on Warm Ischemic Kidney Uncovers Greater eNOS Phosphorylation and Vasodilation

Chatauret

Coudroy

Delpech

et al. 2014

American Journal of Transplantation

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Protection of endothelial cell function may explain the benefits of nonoxygenated hypothermic machine perfusion (MP) for marginal kidney preservation. However, this hypothesis remains to be tested with a preclinical model. We postulated that MP protects the nitric oxide (NO) signaling pathway, altered by static cold storage (CS), and improves renal circulation recovery compared to CS. The endothelium releases the vasodilator NO in response to flow via either increased endothelial NO synthase (eNOS) expression (KLF2-dependent) or activation of eNOS by phosphorylation (via Akt, PKA or AMPK). Using a porcine model of kidney transplantation, including 1 h of warm ischemia and preserved 24 h by CS or MP (n ¼ 5), we reported that MP did not alter the cortical levels of KLF2 and eNOS at the end of preservation, but significantly increased eNOS activating phosphorylation compared to CS. eNOS phosphorylation appeared AMPK-dependent and was concomitant to an increased NO-dependent vasodilation of renal arteries measured, ex situ, at the end of preservation. In vivo, laser Doppler showed that cortical microcirculation was improved at reperfusion in MP kidneys. In conclusion, we demonstrate for the first time, in a large-animal model, that MP protects the NO signaling pathway, confirming the value of MP for marginal kidney preservation.Abbreviations: Akt, protein kinase B; AMPKa, 5 0 -adenosine monophosphate-activated protein kinase alpha; ANOVA, analysis of variance; CS, cold storage; CTL, control; DCD, donation after circulatory death; eNOS, endothelial nitric oxide synthase; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; iNOS, inducible nitric oxide synthase; KLF2, Kruppel-like factor 2; L19, ribosomal protein L19; L-NAME, NGnitro-L-arginine methyl ester; MP, machine perfusion; MPS, machine perfusion solution; NO, nitric oxide; PKA, protein kinase A; RPLPO, ribosomal phosphoprotein large P0 subunit; RT-qPCR, reverse transcriptase quantitative polymerase chain reaction; SEM, standard error of the mean; UW, University of Wisconsin; WI-60, 1 h warm ischemia

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“…Furthermore, several protein kinases, such as PKA and AMPK, have been identified as the upstream kinases of eNOS by phosphorylating eNOS at its activation site (Ser 1177 ) (Li et al, 2012;Thors et al, 2011). Whether BBR protects the proliferative ability of EPCs through the other signaling pathway remains to be investigated.…”

Section: Discussionmentioning

confidence: 99%

Berberine protects endothelial progenitor cell from damage of TNF-α via the PI3K/AKT/eNOS signaling pathway

Xiao¹,

Men²,

Xu³

et al. 2014

European Journal of Pharmacology

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PKA-mediated eNOS phosphorylation in the protection of ischemic preconditioning against no-reflow

Cited by 36 publications

References 48 publications

Limb ischemic preconditioning ameliorates renal microcirculation through activation of PI3K/Akt/eNOS signaling pathway after acute kidney injury

Limb ischemic preconditioning ameliorates renal microcirculation through activation of PI3K/Akt/eNOS signaling pathway after acute kidney injury

Mechanistic Analysis of Nonoxygenated Hypothermic Machine Perfusion’s Protection on Warm Ischemic Kidney Uncovers Greater eNOS Phosphorylation and Vasodilation

Berberine protects endothelial progenitor cell from damage of TNF-α via the PI3K/AKT/eNOS signaling pathway

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