scholarly journals Cyclophilin D and the mitochondrial permeability transition in kidney proximal tubules after hypoxic and ischemic injury

2011 ◽  
Vol 301 (1) ◽  
pp. F134-F150 ◽  
Author(s):  
Jeong Soon Park ◽  
Ratna Pasupulati ◽  
Thorsten Feldkamp ◽  
Nancy F. Roeser ◽  
Joel M. Weinberg
Keyword(s):  
Proximal Tubule ◽  
Mitochondrial Permeability Transition ◽  
Ischemia Reperfusion ◽  
Subsequent Development ◽  
Permeability Transition ◽  
Nonesterified Fatty Acid ◽  
Cyclophilin D ◽  
Mitochondrial Permeability ◽  
Wide Range

Mitochondrial matrix cyclophilin D (CyPD) is known to promote development of the mitochondrial permeability transition (MPT). Kidney proximal tubule cells are especially prone to deleterious effects of mitochondrial damage because of their dependence on oxidative mitochondrial metabolism for ATP production. To clarify the role of CyPD and the MPT in proximal tubule injury during ischemia-reperfusion (I/R) and hypoxia-reoxygenation (H/R), we assessed freshly isolated tubules and in vivo injury in wild-type (WT) and Ppif−/− CyPD-null mice. Isolated mouse tubules developed a sustained, nonesterified fatty acid-mediated energetic deficit after H/R in vitro that could be substantially reversed by delipidated albumin and supplemental citric acid cycle substrates but was not modified by the absence of CyPD. Susceptibility of WT and Ppif−/− tubules to the MPT was increased by H/R but was less in normoxic and H/R Ppif−/− than WT tubules. Correction of the energetic deficit that developed during H/R strongly increased resistance to the MPT. Ppif−/− mice were resistant to I/R injury in vivo spanning a wide range of severity. The data clarify involvement of the MPT in oxygen deprivation-induced tubule cell injury by showing that the MPT does not contribute to the initial bioenergetic deficit produced by H/R but the deficit predisposes to subsequent development of the MPT, which contributes pathogenically to kidney I/R injury in vivo.

scholarly journals The cyclophilin inhibitor NIM-811 increases muscle cell survival with hypoxia in vitro and improves gait performance following ischemia–reperfusion in vivo

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Khairat Bahgat Youssef El Baradie ◽  
Mohammad B. Khan ◽  
Bharati Mendhe ◽  
Jennifer Waller ◽  
Frederick O’Brien ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Cell Survival ◽  
Reperfusion Injury ◽  
Mitochondrial Permeability Transition ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Permeability Transition ◽  
Mitochondrial Permeability

AbstractAcute ischemia–reperfusion injury in skeletal muscle is a significant clinical concern in the trauma setting. The mitochondrial permeability transition inhibitor NIM-811 has previously been shown to reduce ischemic injury in the liver and kidney. The effects of this treatment on skeletal muscle are, however, not well understood. We first used an in vitro model of muscle cell ischemia in which primary human skeletal myoblasts were exposed to hypoxic conditions (1% O2 and 5% CO2) for 6 h. Cells were treated with NIM-811 (0–20 µM). MTS assay was used to quantify cell survival and LDH assay to quantify cytotoxicity 2 h after treatment. Results indicate that NIM-811 treatment of ischemic myotubes significantly increased cell survival and decreased LDH in a dose-dependent manner. We then examined NIM-811 effects in vivo using orthodontic rubber bands (ORBs) for 90 min of single hindlimb ischemia. Mice received vehicle or NIM-811 (10 mg/kg BW) 10 min before reperfusion and 3 h later. Ischemia and reperfusion were monitored using laser speckle imaging. In vivo data demonstrate that mice treated with NIM-811 showed increased gait speed and improved Tarlov scores compared to vehicle-treated mice. The ischemic limbs of female mice treated with NIM-811 showed significantly lower levels of MCP-1, IL-23, IL-6, and IL-1α compared to limbs of vehicle-treated mice. Similarly, male mice treated with NIM-811 showed significantly lower levels of MCP-1 and IL-1a. These findings are clinically relevant as MCP-1, IL-23, IL-6, and IL-1α are all pro-inflammatory factors that are thought to contribute directly to tissue damage after ischemic injury. Results from the in vitro and in vivo experiments suggest that NIM-811 and possibly other mitochondrial permeability transition inhibitors may be effective for improving skeletal muscle salvage and survival after ischemia–reperfusion injury.

scholarly journals Cardioprotective effect of H2S and glutathione synthesis modulation is mediated by inhibition mitochondrial permeability transition pore opening

2020 ◽  
pp. 74-82
Author(s):  
R. Fedichkina ◽  
◽  
Yu. Goshovska ◽  
V. Sagach ◽  
◽  
...  
Keyword(s):  
Mitochondrial Permeability Transition ◽  
Heart Function ◽  
Ischemia Reperfusion ◽  
Permeability Transition ◽  
Cardioprotective Effect ◽  
Glutathione Synthesis ◽  
Mitochondrial Permeability ◽  
Antioxidant Agents ◽  
Wide Range

Hydrogen sulfide (H2S) was recently classified as the third gaseous transmitter produces by two cytosolic cystathionine γ-lyase (CSE) and cystathionine β-synthase, and one mitochondrial enzyme – 3-mercaptopyruvate sulfurtransferase. It was clearly shown that H2S protects against cardiac ischemia/reperfusion (I/R) injury in a wide range of exogenously applied doses of H2S donors. Cell damage within I/R injury is caused by extensive reactive oxygen species (ROS) mainly produced by mitochondria. ROS fleshes are associated with massive opening of mitochondrial permeability transition (MPT) pores and contribute to deterioration of heart function. However, it may be prevented in case of pharmacological inhibition of MPT pores opening. Mixture of mitochondrial metabolites released through the opened MPT pores can be detected in situ as increased optical density of outflow solutions at a wavelength of 245-250 nm and was called mitochondrial factor (MF). One of the most powerful antioxidant agents that preserve redox status in tissues is tripeptide glutathione. It forms in two ATP-depended reactions and exists in two forms reduced and oxidized one. Glutathione and H2S have a common precursor – amino acid L-cysteine. In this study, we used Langendorff isolated rat heart model to investigate the effect of H2S and glutathione synthesis modulation on MPT pores opening in I/R injury. Rats were pretreated intraperitoneally with D,L-propargylglycine (11,3 mg/kg), an inhibitor of H2S-producing enzyme CSE, L-cysteine (121 mg/kg) and buthionine sulfoximine (BSO, 22,2 mg/kg) an inhibitor of first step of glutathione synthesis. Cardiac function, oxygen metabolism and MPT pores opening in situ were measured. We clearly showed that treatment with PAG and L-cysteine provided pharmacological precondition and exerted cardioprotective effect inhibiting MPT pores opening as greatly decreased MF release from isolated heart. Pretreatment with BSO abolished cardioprotective effect of PAG+L-cysteine combination. Absorbance spectra in L-cysteine pretreated group did not differ from the control. Thus, we demonstrate that PAG+L-cysteine induced cardioprotection mediated via inhibition of MPT pores opening.

scholarly journals Intralipid, a Clinically Safe Compound, Protects the Heart Against Ischemia-Reperfusion Injury More Efficiently Than Cyclosporine-A

2012 ◽  
Vol 117 (4) ◽  
pp. 836-846 ◽  
Author(s):  
Jingyuan Li ◽  
Andrea Iorga ◽  
Salil Sharma ◽  
Ji-Youn Youn ◽  
Rod Partow-Navid ◽  
...  
Keyword(s):  
Infarct Size ◽  
Cyclosporine A ◽  
Mitochondrial Permeability Transition Pore ◽  
Mitochondrial Permeability Transition ◽  
Ischemia Reperfusion Injury ◽  
Ex Vivo ◽  
Ischemia Reperfusion ◽  
Permeability Transition ◽  
Mitochondrial Permeability

Background We have recently shown that postischemic administration of intralipid protects the heart against ischemia-reperfusion injury. Here we compared the cardioprotective effects of intralipid with cyclosporine-A, a potent inhibitor of the mitochondrial permeability transition pore opening. Methods In vivo rat hearts or isolated Langendorff-perfused mouse hearts were subjected to ischemia followed by reperfusion with intralipid (0.5%, 1% and 2% ex-vivo, and 20% in vivo), cyclosporine-A (0.2 μM, 0.8 μM, and 1.5 μM ex- vivo and 10 mg/kg in vivo), or vehicle. The hemodynamic function, infarct size, calcium retention capacity, mitochondrial superoxide production, and phosphorylation levels of protein kinase B (Akt)/glycogen synthase kinase-3β (GSK-3β) were measured. The values are mean ± SEM. Results Administration of intralipid at reperfusion significantly reduced myocardial infarct size compared with cyclosporine-A in vivo (infarct size/area at risk)%: 22.9 ± 2.5% vs. 35.2 ± 3.5%; P = 0.030, n = 7/group). Postischemic administration of intralipid at its optimal dose (1%) was more effective than cyclosporine-A (0.8 μM) in protecting the ex vivo heart against ischemia-reperfusion injury, as the rate pressure product at the end of reperfusion was significantly higher (mmHg · beats/min: 12,740 ± 675 [n = 7] vs. 9,203 ± 10,781 [n = 5], P = 0.024), and the infarct size was markedly smaller (17.3 ± 2.9 [n = 7] vs. 29.2 ± 2.7 [n = 5], P = 0.014). Intralipid was as efficient as cyclosporine-A in inhibiting the mitochondrial permeability transition pore opening (calcium retention capacity = 280 ± 8.2 vs. 260.3 ± 2.9 nmol/mg mitochondria protein in cyclosporine-A, P = 0.454, n = 6) and in reducing cardiac mitochondrial superoxide production. Unlike intralipid, which increased phosphorylation of Akt (6-fold) and GSK-3β (5-fold), cyclosporine-A had no effect on the activation of these prosurvival kinases. Conclusions Although intralipid inhibits the opening of the mitochondrial permeability transition pore as efficiently as cyclosporine-A, intralipid is more effective in reducing the infarct size and improving the cardiac functional recovery.

scholarly journals Regulation of the mitochondrial permeability transition in kidney proximal tubules and its alteration during hypoxia-reoxygenation

2009 ◽  
Vol 297 (6) ◽  
pp. F1632-F1646 ◽  
Author(s):  
Thorsten Feldkamp ◽  
Jeong Soon Park ◽  
Ratna Pasupulati ◽  
Daniela Amora ◽  
Nancy F. Roeser ◽  
...  
Keyword(s):  
Complex I ◽  
Mitochondrial Permeability Transition ◽  
Permeability Transition ◽  
Proximal Tubules ◽  
Cyclophilin D ◽  
Mitochondrial Permeability ◽  
Endogenous Metabolites ◽  
Hypoxia Reoxygenation ◽  
Kidney Proximal Tubules

Development of the mitochondrial permeability transition (MPT) can importantly contribute to lethal cell injury from both necrosis and apoptosis, but its role varies considerably with both the type of cell and type of injury, and it can be strongly opposed by the normally abundant endogenous metabolites ADP and Mg2+. To better characterize the MPT in kidney proximal tubule cells and assess its contribution to injury to them, we have refined and validated approaches to follow the process in whole kidney proximal tubules and studied its regulation in normoxic tubules and after hypoxia-reoxygenation (H/R). Physiological levels of ADP and Mg2+ greatly decreased sensitivity to the MPT. Inhibition of cyclophilin D by cyclosporine A (CsA) effectively opposed the MPT only in the presence of ADP and/or Mg2+. Nonesterified fatty acids (NEFA) had a large role in the decreased resistance to the MPT seen after H/R irrespective of the available substrate or the presence of ADP, Mg2+, or CsA, but removal of NEFA was less effective at restoring normal resistance to the MPT in the presence of electron transport complex I-dependent substrates than with succinate. The data indicate that the NEFA accumulation that occurs during both hypoxia in vitro and ischemic acute kidney injury in vivo is a critical sensitizing factor for the MPT that overcomes the antagonistic effect of endogenous metabolites and cyclophilin D inhibition, particularly in the presence of complex I-dependent substrates, which predominate in vivo.

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