Na+/Ca2+ exchange inhibitor, KB-R7943, attenuates contrast-induced acute  kidney injury

Yang, Dingwei; Yang, Dingping; Jia, Ru; Tan, Ji

doi:10.5301/jn.5000259

Cited by 26 publications

(26 citation statements)

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“…It has been proven that the ER stress-induced apoptosis can be mediated by ROS [22] and that oxidative stress plays an important role in the pathogenesis of CI-AKI [12,23]. In the present study, the role of ROS in the ER stress-induced apoptosis in iopromide-treated NRK-52E cells was investigated.…”

Section: Discussionmentioning

confidence: 99%

Role of Reactive Oxygen Species-Mediated Endoplasmic Reticulum Stress in Contrast-Induced Renal Tubular Cell Apoptosis

Yang

et al. 2014

Nephron Exp Nephrol

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Background: Renal tubular cell apoptosis is a key mechanism of contrast-induced acute kidney injury. It has been reported that endoplasmic reticulum (ER) stress is the underlying mechanism of high osmolar contrast-induced renal tubular cell apoptosis. Whether ER stress is involved in low osmolar contrast-induced renal tubular cell injury remains unclear. In the present study, the roles of ER stress in iopromide-induced (a low osmolar contrast) renal tubular cell apoptosis and the effects of N-acetylcysteine (NAC) on ER stress were investigated. Methods: NRK-52E cells were exposed to different concentrations of iopromide [50, 100 and 150 mg iodine (I)/ml] for 4 h. In a separate experiment, NRK-52E cells were exposed to iopromide (100 mg I/ml, 4 h) with or without NAC (10 mmol/l). NAC was added 1 h before incubation with iopromide. Apoptosis was determined by Hoechst staining and flow cytometry. The intracellular formation of reactive oxygen species (ROS) was detected by confocal microscopy with fluorescent probe CM-H2DCFDA. The expression of glucose-regulated protein 78 (GRP78) and CAAT/enhancer-binding protein homologous protein (CHOP) was determined by Western blot. Results: Iopromide induced NRK-52E cell apoptosis in a concentration-dependent manner. The intracellular ROS production increased significantly following iopromide exposure in the NRK-52E cells. Significantly increased expressions of GRP78 and CHOP were observed in the NRK-52E cells exposed to iopromide for 4 h; NAC attenuated iopromide-induced NRK-52E cell apoptosis by inhibiting the overproduction of intracellular ROS and subsequently suppressing the overexpression of GRP78 and CHOP. Conclusion: ROS-mediated ER stress is involved in contrast-induced renal tubular cell apoptosis.

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Section: Discussionmentioning

confidence: 99%

Role of Reactive Oxygen Species-Mediated Endoplasmic Reticulum Stress in Contrast-Induced Renal Tubular Cell Apoptosis

Yang

et al. 2014

Nephron Exp Nephrol

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“…The Na + /Ca 2+ exchanger system is one of the main pathways of intracellular Ca 2+ overload. It has been demonstrated that in rats the pretreatment with KB-R7943, an inhibitor of the Na + /Ca 2+ exchanger system, significantly and dose-dependently suppressed the increase of serum creatinine following diatrizoate administration [210]. The increase in intracellular calcium provokes a vasoconstrictive response in intrarenal circulation and would be an important mediator of epithelial cell apoptosis and necrosis.…”

Section: Contrast-induced Nephropathymentioning

confidence: 99%

Side Effects of Radiographic Contrast Media: Pathogenesis, Risk Factors, and Prevention

Andreucci

Solomon

Tasanarong

2014

BioMed Research International

217

226

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Radiocontrast media (RCM) are medical drugs used to improve the visibility of internal organs and structures in X-ray based imaging techniques. They may have side effects ranging from itching to a life-threatening emergency, known as contrast-induced nephropathy (CIN). We define CIN as acute renal failure occurring within 24–72 hrs of exposure to RCM that cannot be attributed to other causes. It usually occurs in patients with preexisting renal impairment and diabetes. The mechanisms underlying CIN include reduction in medullary blood flow leading to hypoxia and direct tubule cell damage and the formation of reactive oxygen species. Identification of patients at high risk for CIN is important. We have reviewed the risk factors and procedures for prevention, providing a long list of references enabling readers a deep evaluation of them both. The first rule to follow in patients at risk of CIN undergoing radiographic procedure is monitoring renal function by measuring serum creatinine and calculating the eGFR before and once daily for 5 days after the procedure. It is advised to discontinue potentially nephrotoxic medications, to choose radiocontrast media at lowest dosage, and to encourage oral or intravenous hydration. In high-risk patients N-acetylcysteine may also be given.

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“…The rationale is based on the fact that while in normal subjects, the Na + –Ca 2+ exchanger pumps Ca 2+ outside the renal tubular epithelial cells to keep intracellular Ca 2+ low, under the effect of contrast drugs the Na + –Ca 2+ exchanger can reversibly extrude Na + for Ca 2+ influx, thereby leading to intracellular Ca 2+ overload, which is considered a key factor in ischemic cell injury and in CI-AKI 135–137. (Figure 1).…”

Section: Prevention Of Ci-akimentioning

confidence: 99%

Update on the renal toxicity of iodinated contrast drugs used in clinical medicine

Andreucci¹,

Faga²,

Serra

et al. 2017

DHPS

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An important side effect of diagnostic contrast drugs is contrast-induced acute kidney injury (CI-AKI; a sudden decrease in renal function) occurring 48–72 hours after injection of a contrast drug that cannot be attributed to other causes. Its existence has recently been challenged, because of some retrospective studies in which the incidence of AKI was not different between subjects who received a contrast drug and those who did not, even using propensity score matching to prevent selection bias. For some authors, only patients with estimated glomerular filtration rate <30 mL/min/1.73 m2 are at significant risk of CI-AKI. Most agree that when renal function is normal, there is no CI-AKI risk. Many experimental studies, however, are in favor of the existence of CI-AKI. Contrast drugs have been shown to cause the following changes: renal vasoconstriction, resulting in a rise in intrarenal resistance (decrease in renal blood flow and glomerular filtration rate and medullary hypoxia); epithelial vacuolization and dilatation and necrosis of proximal tubules; potentiation of angiotensin II effects, reducing nitric oxide (NO) and causing direct constriction of descending vasa recta, leading to formation of reactive oxygen species in isolated descending vasa recta of rats microperfused with a solution of iodixanol; increasing active sodium reabsorption in the thick ascending limbs of Henle’s loop (increasing O2 demand and consequently medullary hypoxia); direct cytotoxic effects on endothelial and tubular epithelial cells (decrease in release of NO in vasa recta); and reducing cell survival, due to decreased activation of Akt and ERK1/2, kinases involved in cell survival/proliferation. Prevention is mainly based on extracellular volume expansion, statins, and N-acetylcysteine; conflicting results have been obtained with nebivolol, furosemide, calcium-channel blockers, theophylline, and hemodialysis.

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Na+/Ca2+ exchange inhibitor, KB-R7943, attenuates contrast-induced acute  kidney injury

Abstract: Activation of the reverse mode of NCX, followed by ET-1 overproduction and increased oxidative stress, seems to play an important role in the pathogenesis of CI-AKI. The inhibitor of the reverse mode of NCX, KB-R7943, has renoprotective effects on CI-AKI.

Cited by 26 publications

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Role of Reactive Oxygen Species-Mediated Endoplasmic Reticulum Stress in Contrast-Induced Renal Tubular Cell Apoptosis

Role of Reactive Oxygen Species-Mediated Endoplasmic Reticulum Stress in Contrast-Induced Renal Tubular Cell Apoptosis

Side Effects of Radiographic Contrast Media: Pathogenesis, Risk Factors, and Prevention

Update on the renal toxicity of iodinated contrast drugs used in clinical medicine

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Na+/Ca2+ exchange inhibitor, KB-R7943, attenuates contrast-induced acute kidney injury

Abstract: Activation of the reverse mode of NCX, followed by ET-1 overproduction and increased oxidative stress, seems to play an important role in the pathogenesis of CI-AKI. The inhibitor of the reverse mode of NCX, KB-R7943, has renoprotective effects on CI-AKI.

Cited by 26 publications

References 0 publications

Role of Reactive Oxygen Species-Mediated Endoplasmic Reticulum Stress in Contrast-Induced Renal Tubular Cell Apoptosis

Role of Reactive Oxygen Species-Mediated Endoplasmic Reticulum Stress in Contrast-Induced Renal Tubular Cell Apoptosis

Side Effects of Radiographic Contrast Media: Pathogenesis, Risk Factors, and Prevention

Update on the renal toxicity of iodinated contrast drugs used in clinical medicine

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Na+/Ca2+ exchange inhibitor, KB-R7943, attenuates contrast-induced acute  kidney injury