Hydroxyfasudil-Mediated Inhibition of ROCK1 and ROCK2 Improves Kidney Function in Rat Renal Acute Ischemia-Reperfusion Injury

Kentrup, Dominik; Reuter, Stefan; Schnöckel, Uta; Grabner, Alexander; Edemir, Bayram; Pavenstädt, Hermann; Schober, Otmar; Schäfers, Michael; Schlatter, Eberhard; Büssemaker, Eckhart

doi:10.1371/journal.pone.0026419

Cited by 28 publications

(22 citation statements)

References 60 publications

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“…Fasudil is a potent Rho-associated protein kinase (ROCK) inhibitor [8,9,10,11,12,13] and vasodilator and has been used for the treatment of cerebral vasospasm [9] and many other diseases, such as cancer [14,15], allergy [16] and inflammation [17,18]. The systematic administration of Fasudil was reported protecting mice from experimental autoimmune encephalomyelitis (EAE) and shifting macrophages from M1 to M2 [19].…”

Section: Introductionmentioning

confidence: 99%

WITHDRAWN: Macrophage-targeting Fasudil treatment protects liver from the ischemia/reperfusion injury by promoting M2 macrophage polarization

et al. 2018

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Macrophages play essential roles in the generation and resolution of inflammation. Ischemia-reperfusion injury (IRI) triggers a systemic inflammatory response and leads to cellular injury and organ failure.During surgical procedures of the liver, such as hepatic resection and liver transplantation, IRI leads to the dysfunction of the liver. Rho-associated protein kinase (ROCK) inhibitors were reported protecting the liver from IRI. However, the systematic administration of ROCK inhibitors causes severe hypotension.Here, using Fasudil carried liposomes, we specifically inhibited the ROCK-II expression in Kupffer cells and blood monocytes. Through this macrophage/monocyte specific treatment of Fasudil, we successfully protected the liver from IRI by shifting Kupffer cells/monocytes from M1/classical to M2/patrolling phenotype in the liver and peripheral blood. Our finding provides novel insights into the macrophage/monocyte-specific drug delivery and the treatment of liver IRI.

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Section: Introductionmentioning

confidence: 99%

WITHDRAWN: Macrophage-targeting Fasudil treatment protects liver from the ischemia/reperfusion injury by promoting M2 macrophage polarization

et al. 2018

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“…Patients with AHF have increased circulating levels of norepinephrine, renin and aldosterone, and lowering these neurohormones during 1 to 3 days with vasodilator and diuretic therapy has been associated with improved hemodynamics and outcomes. 37 Indeed, quiescence of neurohormonally mediated vascular inflammation may be reflected by reduced serum creatinine, 38,39 although clinical studies in resistant hypertension have shown no improvement in renal function with renal sympathetic denervation. 40 Whether this pathophysiologic link is present in AHF remains to be determined.…”

Section: Discussionmentioning

confidence: 99%

Renal Function Trajectories and Clinical Outcomes in Acute Heart Failure

Givertz

Postmus

Hillege

et al. 2014

Circ: Heart Failure

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Background-Prior studies have demonstrated adverse risk associated with baseline and worsening renal function in acute heart failure, but none has modeled the trajectories of change in renal function and their impact on outcomes. Methods and Results-We used linear mixed models of serial measurements of blood urea nitrogen and creatinine to describe trajectories of renal function in 1962 patients with acute heart failure and renal dysfunction enrolled in the Placebo-Controlled Randomized Study of the Selective A 1 Adenosine Receptor Antagonist Rolofylline for Patients Hospitalized with Acute Decompensated Heart Failure and Volume Overload to Assess Treatment Effect on Congestion and Renal Function study. We assessed risk of 180-day mortality and 60-day cardiovascular or renal readmission and used Cox regression to determine association between renal trajectories and outcomes. Compared with patients alive at 180 days, patients who died were older, had lower blood pressure and ejection fraction, and higher creatinine levels at baseline. On average for the entire cohort, creatinine rose from days 1 to 3 and increased further after discharge, with the trajectory dependent on the day of discharge. Blood urea nitrogen, creatinine, and the rate of change in creatinine from baseline were the strongest independent predictors of 180-day mortality and 60-day readmission, whereas the rate of change of blood urea nitrogen from baseline was not predictive of outcomes. Baseline blood urea nitrogen >35 mg/ dL and increase in creatinine >0.1 mg/dL per day increased the risk of mortality, whereas stable or decreasing creatinine was associated with reduced risk. Conclusions-Patients with acute heart failure and renal dysfunction demonstrate variable rise and fall in renal indices during and immediately after hospitalization. Risk of morbidity and mortality can be predicted based on baseline renal function and creatinine trajectory during the first 7 days. Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifiers: NCT00328692 and NCT00354458.(Circ Heart Fail. 2014;7:59-67.)

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“…21 To evaluate the possible relationship between Klf4 and these molecules, we determined the expression of these proteins in Klf4 cKO and control mice. Results showed that Hmox1 expression was increased by renal I/R injury and that I/R injuryinduced Hmox1 expression was unaffected by fluvastatin ( Figure 7, A and B).…”

Section: Inflammatory Cell Accumulation and Expression Of Cell Adhesionmentioning

confidence: 99%

Endothelial Krüppel-Like Factor 4 Mediates the Protective Effect of Statins against Ischemic AKI

Yoshida

Yamashita

Iwai

et al. 2015

JASN

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Endothelial cells participate in the pathophysiology of ischemic AKI by increasing the expression of cell adhesion molecules and by recruiting inflammatory cells. We previously showed that endothelial Krüppel-like factor 4 (Klf4) regulates vascular cell adhesion molecule 1 (Vcam1) expression and neointimal formation after carotid injury. In this study, we determined whether endothelial Klf4 is involved in ischemic AKI using endothelial Klf4 conditional knockout (Klf4 cKO) mice generated by breeding Tek-Cre mice and Klf4 floxed mice. Klf4 cKO mice were phenotypically normal before surgery. However, after renal ischemia-reperfusion injury, Klf4 cKO mice exhibited elevated serum levels of urea nitrogen and creatinine and aggravated renal histology compared with those of Klf4 floxed controls. Moreover, Klf4 cKO mice exhibited enhanced accumulation of neutrophils and lymphocytes and elevated expression of cell adhesion molecules, including Vcam1 and Icam1, in injured kidneys. Notably, statins ameliorated renal ischemia-reperfusion injury in control mice but not in Klf4 cKO mice. Mechanistic analyses in cultured endothelial cells revealed that statins increased KLF4 expression and that KLF4 mediated the suppressive effect of statins on TNFa-induced VCAM1 expression by reducing NF-kB binding to the VCAM1 promoter. These results provide evidence that endothelial Klf4 is renoprotective and mediates statin-induced protection against ischemic AKI by regulating the expression of cell adhesion molecules and concomitant recruitment of inflammatory cells.

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Hydroxyfasudil-Mediated Inhibition of ROCK1 and ROCK2 Improves Kidney Function in Rat Renal Acute Ischemia-Reperfusion Injury

Cited by 28 publications

References 60 publications

WITHDRAWN: Macrophage-targeting Fasudil treatment protects liver from the ischemia/reperfusion injury by promoting M2 macrophage polarization

WITHDRAWN: Macrophage-targeting Fasudil treatment protects liver from the ischemia/reperfusion injury by promoting M2 macrophage polarization

Renal Function Trajectories and Clinical Outcomes in Acute Heart Failure

Endothelial Krüppel-Like Factor 4 Mediates the Protective Effect of Statins against Ischemic AKI

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