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Hydroxyfasudil-mediated inhibition of ROCK1 and ROCK2 improves kidney function in rat renal acute ischemia-reperfusion injury.

Kentrup D, Reuter S, Schnöckel U, Grabner A, Edemir B, Pavenstädt H, Schober O, Schäfers M, Schlatter E, Büssemaker E - PLoS ONE (2011)

Bottom Line: Attraction to and transmigration of immune cells into the interstitium is associated with increased vascular permeability and loss of endothelial and tubular epithelial cell integrity.Using an IRI-based animal model of AKI in male Sprague Dawley rats, animals treated with hydroxyfasudil showed reduced proteinuria and polyuria as well as increased urine osmolarity when compared with sham-treated animals.Moreover, endothelial leakage and renal inflammation was significantly reduced as determined by histology, (18)F-fluordesoxyglucose-microautoradiography, Evans Blue, and real-time PCR analysis.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine D, Experimental Nephrology, University of Münster, Münster, Germany.

ABSTRACT
Renal ischemia-reperfusion (IR) injury (IRI) is a common and important trigger of acute renal injury (AKI). It is inevitably linked to transplantation. Involving both, the innate and the adaptive immune response, IRI causes subsequent sterile inflammation. Attraction to and transmigration of immune cells into the interstitium is associated with increased vascular permeability and loss of endothelial and tubular epithelial cell integrity. Considering the important role of cytoskeletal reorganization, mainly regulated by RhoGTPases, in the development of IRI we hypothesized that a preventive, selective inhibition of the Rho effector Rho-associated coiled coil containing protein kinase (ROCK) by hydroxyfasudil may improve renal IRI outcome. Using an IRI-based animal model of AKI in male Sprague Dawley rats, animals treated with hydroxyfasudil showed reduced proteinuria and polyuria as well as increased urine osmolarity when compared with sham-treated animals. In addition, renal perfusion (as assessed by (18)F-fluoride Positron Emission Tomography (PET)), creatinine- and urea-clearances improved significantly. Moreover, endothelial leakage and renal inflammation was significantly reduced as determined by histology, (18)F-fluordesoxyglucose-microautoradiography, Evans Blue, and real-time PCR analysis. We conclude from our study that ROCK-inhibition by hydroxyfasudil significantly improves kidney function in a rat model of acute renal IRI and is therefore a potential new therapeutic option in humans.

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Effects of ischemia-reperfusion injury and ROCK-inhibition on metabolic parameters.IRI significantly affected kidney function (as assessed by creatinine-clearance, urea-clearance, urine osmolarity and urine protein excretion on POD0-4) whereas the renal function of HF-treated animals was less severe affected. Starting on POD 1, HF-treated animals had improved creatinine-clearance (NxIRHF: 0.38±0.04 ml/min/100 g vs. NxIRCTR: 0.14±0.03 ml/min/100 g, n = 6) as well as urea-clearance (NxIRHF: 0.17±0.02 ml/min/100 g vs. NxIRCTR: 0.06±0.01 ml/min/100 g, n = 6) when compared to vehicle-treated rats. Moreover, the HF-treated rats showed a better preserved renal urinary concentrating capacity. Interestingly, proteinuria, which initially occurred in the NxIRCTR group was absent in NxIRHF. In summary, kidney injury was significantly attenuated by HF application leading to a distinct faster recovery of renal function. Values are expressed as mean ± SEM; *indicates significance to NxIRCTR POD0.
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pone-0026419-g001: Effects of ischemia-reperfusion injury and ROCK-inhibition on metabolic parameters.IRI significantly affected kidney function (as assessed by creatinine-clearance, urea-clearance, urine osmolarity and urine protein excretion on POD0-4) whereas the renal function of HF-treated animals was less severe affected. Starting on POD 1, HF-treated animals had improved creatinine-clearance (NxIRHF: 0.38±0.04 ml/min/100 g vs. NxIRCTR: 0.14±0.03 ml/min/100 g, n = 6) as well as urea-clearance (NxIRHF: 0.17±0.02 ml/min/100 g vs. NxIRCTR: 0.06±0.01 ml/min/100 g, n = 6) when compared to vehicle-treated rats. Moreover, the HF-treated rats showed a better preserved renal urinary concentrating capacity. Interestingly, proteinuria, which initially occurred in the NxIRCTR group was absent in NxIRHF. In summary, kidney injury was significantly attenuated by HF application leading to a distinct faster recovery of renal function. Values are expressed as mean ± SEM; *indicates significance to NxIRCTR POD0.

Mentions: To estimate renal function, blood and urine samples were analyzed at baseline, as well as after IRI on POD1 and 4. Before starting the interventions, parameters did not differ between groups (Table 2). One week after uninephrectomy no significant differences to healthy animals were observed. Due to the IRI renal function significantly decreased in all intervention groups by POD1. Recovery of renal function started immediately thereafter leading to a continuous decrease of CrS and BUN until POD4. However, HF-treated rats showed a significantly improved creatinine-clearance as well as urea-clearance. Furthermore, urine osmolarity, proteinuria, and polyuria improved significantly as shown in figure 1 and table 2. To sum up, renal damage was reduced and kidney function of HF-treated animals recovered faster than in controls. While kidney function normalized already on POD2 in NxIRHF (no significant differences compared to baseline values), kidney function of untreated rats failed to normalize even 48 h later at least for some parameters.


Hydroxyfasudil-mediated inhibition of ROCK1 and ROCK2 improves kidney function in rat renal acute ischemia-reperfusion injury.

Kentrup D, Reuter S, Schnöckel U, Grabner A, Edemir B, Pavenstädt H, Schober O, Schäfers M, Schlatter E, Büssemaker E - PLoS ONE (2011)

Effects of ischemia-reperfusion injury and ROCK-inhibition on metabolic parameters.IRI significantly affected kidney function (as assessed by creatinine-clearance, urea-clearance, urine osmolarity and urine protein excretion on POD0-4) whereas the renal function of HF-treated animals was less severe affected. Starting on POD 1, HF-treated animals had improved creatinine-clearance (NxIRHF: 0.38±0.04 ml/min/100 g vs. NxIRCTR: 0.14±0.03 ml/min/100 g, n = 6) as well as urea-clearance (NxIRHF: 0.17±0.02 ml/min/100 g vs. NxIRCTR: 0.06±0.01 ml/min/100 g, n = 6) when compared to vehicle-treated rats. Moreover, the HF-treated rats showed a better preserved renal urinary concentrating capacity. Interestingly, proteinuria, which initially occurred in the NxIRCTR group was absent in NxIRHF. In summary, kidney injury was significantly attenuated by HF application leading to a distinct faster recovery of renal function. Values are expressed as mean ± SEM; *indicates significance to NxIRCTR POD0.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3198766&req=5

pone-0026419-g001: Effects of ischemia-reperfusion injury and ROCK-inhibition on metabolic parameters.IRI significantly affected kidney function (as assessed by creatinine-clearance, urea-clearance, urine osmolarity and urine protein excretion on POD0-4) whereas the renal function of HF-treated animals was less severe affected. Starting on POD 1, HF-treated animals had improved creatinine-clearance (NxIRHF: 0.38±0.04 ml/min/100 g vs. NxIRCTR: 0.14±0.03 ml/min/100 g, n = 6) as well as urea-clearance (NxIRHF: 0.17±0.02 ml/min/100 g vs. NxIRCTR: 0.06±0.01 ml/min/100 g, n = 6) when compared to vehicle-treated rats. Moreover, the HF-treated rats showed a better preserved renal urinary concentrating capacity. Interestingly, proteinuria, which initially occurred in the NxIRCTR group was absent in NxIRHF. In summary, kidney injury was significantly attenuated by HF application leading to a distinct faster recovery of renal function. Values are expressed as mean ± SEM; *indicates significance to NxIRCTR POD0.
Mentions: To estimate renal function, blood and urine samples were analyzed at baseline, as well as after IRI on POD1 and 4. Before starting the interventions, parameters did not differ between groups (Table 2). One week after uninephrectomy no significant differences to healthy animals were observed. Due to the IRI renal function significantly decreased in all intervention groups by POD1. Recovery of renal function started immediately thereafter leading to a continuous decrease of CrS and BUN until POD4. However, HF-treated rats showed a significantly improved creatinine-clearance as well as urea-clearance. Furthermore, urine osmolarity, proteinuria, and polyuria improved significantly as shown in figure 1 and table 2. To sum up, renal damage was reduced and kidney function of HF-treated animals recovered faster than in controls. While kidney function normalized already on POD2 in NxIRHF (no significant differences compared to baseline values), kidney function of untreated rats failed to normalize even 48 h later at least for some parameters.

Bottom Line: Attraction to and transmigration of immune cells into the interstitium is associated with increased vascular permeability and loss of endothelial and tubular epithelial cell integrity.Using an IRI-based animal model of AKI in male Sprague Dawley rats, animals treated with hydroxyfasudil showed reduced proteinuria and polyuria as well as increased urine osmolarity when compared with sham-treated animals.Moreover, endothelial leakage and renal inflammation was significantly reduced as determined by histology, (18)F-fluordesoxyglucose-microautoradiography, Evans Blue, and real-time PCR analysis.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine D, Experimental Nephrology, University of Münster, Münster, Germany.

ABSTRACT
Renal ischemia-reperfusion (IR) injury (IRI) is a common and important trigger of acute renal injury (AKI). It is inevitably linked to transplantation. Involving both, the innate and the adaptive immune response, IRI causes subsequent sterile inflammation. Attraction to and transmigration of immune cells into the interstitium is associated with increased vascular permeability and loss of endothelial and tubular epithelial cell integrity. Considering the important role of cytoskeletal reorganization, mainly regulated by RhoGTPases, in the development of IRI we hypothesized that a preventive, selective inhibition of the Rho effector Rho-associated coiled coil containing protein kinase (ROCK) by hydroxyfasudil may improve renal IRI outcome. Using an IRI-based animal model of AKI in male Sprague Dawley rats, animals treated with hydroxyfasudil showed reduced proteinuria and polyuria as well as increased urine osmolarity when compared with sham-treated animals. In addition, renal perfusion (as assessed by (18)F-fluoride Positron Emission Tomography (PET)), creatinine- and urea-clearances improved significantly. Moreover, endothelial leakage and renal inflammation was significantly reduced as determined by histology, (18)F-fluordesoxyglucose-microautoradiography, Evans Blue, and real-time PCR analysis. We conclude from our study that ROCK-inhibition by hydroxyfasudil significantly improves kidney function in a rat model of acute renal IRI and is therefore a potential new therapeutic option in humans.

Show MeSH
Related in: MedlinePlus