scholarly journals Transcriptional Profiles in Ischemia/Reperfusion-Injured Murine Kidneys Synergistically Protected by Erythropoietin Derived Peptide CHBP and Caspase-3 siRNA

2020 ◽  
Author(s):  
Yuanyuan Wu ◽  
Weiwei Chen ◽  
Yufang Zhang ◽  
Aifen Liu ◽  
Cheng Yang ◽  
...  
Keyword(s):  
Renal Function ◽  
Caspase 3 ◽  
Early Stage ◽  
Synergistic Effects ◽  
Ischemia Reperfusion ◽  
Combined Treatment ◽  
Specific Treatment ◽  
Kidney Injury ◽  
Negative Control ◽  
Active Caspase

Abstract Background: Target-specific treatment is not available for acute kidney injury (AKI). A novel erythropoietin-derived cyclic helix B surface peptide (CHBP) protects kidneys against AKI subjected to different causes. Herein, we investigated the transcriptional profile of renoprotection induced by CHBP and its potential synergistic effects with caspase-3 siRNA (CASP3siRNA) on ischemia/reperfusion (IR) injury associated AKI. Methods: A mouse renal IR model was established by clamping bilateral pedicles for 30 min and reperfusion for 48 h. 0.03 mg/kg of CASP3siRNA/negative control (NCsiRNA) was injected via tail vein 2 h pre-surgery, with/without 24 nmol/kg of CHBP administered to peritoneal cavity at 15 min post reperfusion. The transcriptomic profile in kidneys was assessed by affymetrix gene chips, along with renal function, histology, active caspase-3 and HMGB1.Results: CHBP or CASP3siRNA significantly improved renal function and structure, with decreased caspase-3 and HMGB1 in IR kidneys. Combined treatment of CHBP and CASP3siRNA further preserved kidney structure, and reduced active caspase-3 and HMGB1. Furthermore, fold change > 1.414 and P < 0.05 were used to identify differentially expressed genes (DEGs). In IR kidneys, 281 DEGs induced by CHBP were mainly involved in promoting cell division and improving cellular function and metabolism (up-regulated STAT5B and SLC22A7). The additional administration of CASP3siRNA caused 504 and 418 DEGs in IR + CHBP kidneys with or without NCsiRNA, with 37 genes in common. These DEGs were associated with modulated apoptosis and inflammation (up-regulated BCL6，SLPI and SERPINA3M), and immunity, injury and microvascular homeostasis (up-regulated CFH and GREM1, and down-regulated ANGPTL2). Conclusions: This proof-of-effect study indicated that the synergistic renoprotection of CHBP and CASP3siRNA at the early stage of IR-induced AKI. Underlying genes, BCL6, SLPI, SERPINA3M, GREM1 and ANGPTL2, might be potential new biomarkers for clinical applications.

Potent Therapy and Transcriptional Profile of Combined Erythropoietin Derived Peptide CHBP and Caspase-3 siRNA against Kidney Ischemia/Reperfusion Injury in mice

2020 ◽  
Author(s):  
Yuanyuan Wu ◽  
Weiwei Chen ◽  
Yufang Zhang ◽  
Aifen Liu ◽  
Cheng Yang ◽  
...  
Keyword(s):  
Caspase 3 ◽  
Ischemia Reperfusion Injury ◽  
Early Stage ◽  
Synergistic Effects ◽  
Ischemia Reperfusion ◽  
Combined Treatment ◽  
Specific Treatment ◽  
Transcriptional Profile ◽  
Apoptosis And Inflammation ◽  
Active Caspase

Abstract Cause-specific treatment and timely diagnosis are still not available for acute kidney injury (AKI) apart from supportive therapy and serum creatinine measurement. A novel erythropoietin-derived cyclic helix B surface peptide (CHBP) protects kidneys against AKI with different causes, but the underlying mechanism is not fully defined. Herein, we investigated the transcriptional profile of renoprotection induced by CHBP and its potential synergistic effects with siRNA targeting caspase-3, an executing enzyme of apoptosis and inflammation, (CASP3siRNA) on ischemia/reperfusion (IR)-induced AKI. Utilizing a mouse model with 30-min renal bilateral ischemia and 48-h reperfusion, the renoprotection of CHBP or CASP3siRNA was demonstrated in renal function and structure, active caspase-3 and HMGB1 expression. Combined treatment of CHBP and CASP3siRNA further preserved kidney structure, and reduced active caspase-3 and HMGB1. Furthermore, differentially expressed genes (DEGs) were identified with fold change > 1.414 and P < 0.05. In IR kidneys, 281 DEGs induced by CHBP were mainly involved in promoting cell division and improving cellular function and metabolism (up-regulated STAT5B and SLC22A7). The additional administration of CASP3siRNA caused 504 and 418 DEGs in IR + CHBP kidneys with or without NCsiRNA, with 37 genes in common. These DEGs were associated with modulated apoptosis and inflammation (up-regulated BCL6, SLPI and SERPINA3M), and immunity, injury and microvascular homeostasis (up-regulated CFH and GREM1, and down-regulated ANGPTL2). This proof-of-effect study indicated the potent renoprotection of CASP3siRNA upon CHBP at the early stage of IR-induced AKI. Underlying genes, BCL6, SLPI, SERPINA3M, GREM1 and ANGPTL2, might be potential new biomarkers for clinical applications.

scholarly journals Comment on “Nuclear receptor PXR targets AKR1B7 to protect mitochondrial metabolism and renal function in AKI”

2021 ◽  
Vol 13 (593) ◽  
pp. eabd0214
Author(s):  
Zhilin Luan ◽  
Wenhua Ming ◽  
Cong Zhang ◽  
Xiaoxiao Huo ◽  
Feng Zheng ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Renal Function ◽  
Nuclear Receptor ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Pregnane X Receptor ◽  
Mitochondrial Metabolism

The nuclear pregnane X receptor may not protect against ischemia/reperfusion-induced acute kidney injury in mice.

scholarly journals Protective Effects of HBSP on Ischemia Reperfusion and Cyclosporine A Induced Renal Injury

2013 ◽  
Vol 2013 ◽  
pp. 1-12 ◽  
Author(s):  
Yuanyuan Wu ◽  
Junlin Zhang ◽  
Feng Liu ◽  
Cheng Yang ◽  
Yufang Zhang ◽  
...  
Keyword(s):  
Cyclosporine A ◽  
Caspase 3 ◽  
Interstitial Fibrosis ◽  
Ischemia Reperfusion ◽  
Inflammatory Cells ◽  
Protective Effects ◽  
Tubulointerstitial Damage ◽  
Apoptosis And Inflammation ◽  
The Right ◽  
Active Caspase

Ischemia reperfusion (IR) and cyclosporine A (CsA) injuries are unavoidable in kidney transplantation and are associated with allograft dysfunction. Herein, the effect and mechanism of a novel tissue protective peptide, helix B surface peptide (HBSP) derived from erythropoietin, were investigated in a rat model. The right kidney was subjected to 45 min ischemia, followed by left nephrectomy and 2-week reperfusion, with or without daily treatment of CsA 25 mg/kg and/or HBSP 8 nmol/kg. Blood urea nitrogen was increased by CsA but decreased by HBSP at 1 week and 2 weeks, while the same changes were revealed in urinary protein/creatinine only at 2 weeks. HBSP also significantly ameliorated tubulointerstitial damage and interstitial fibrosis, which were gradually increased by IR and CsA. In addition, apoptotic cells, infiltrated inflammatory cells, and active caspase-3+ cells were greatly reduced by HBSP in the both IR and IR + CsA groups. The 17 kD active caspase-3 protein was decreased by HBSP in the IR and IR + CsA kidneys, with decreased mRNA only in the IR + CsA kidneys. Taken together, it has been demonstrated, for the first time, that HBSP effectively improved renal function and tissue damage caused by IR and/or CsA, which might be through reducing caspase-3 activation and synthesis, apoptosis, and inflammation.

scholarly journals A Novel Antioxidant Protects Against Contrast Medium-Induced Acute Kidney Injury in Rats

2020 ◽  
Vol 11 ◽  
Author(s):  
Shuo Huang ◽  
Yanyan Tang ◽  
Tianjun Liu ◽  
Ning Zhang ◽  
Xueyan Yang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Acute Kidney Injury ◽  
Superoxide Dismutase ◽  
Renal Function ◽  
Cytochrome C ◽  
Caspase 3 ◽  
Mitochondrial Protein ◽  
Kidney Injury ◽  
High Efficient ◽  
Superoxide Dismutase 2

Many studies proposed that oxidative stress and apoptosis are key mechanisms in the pathogenesis of contrast-induced acute kidney injury (CI-AKI). Xylose-pyrogallol conjugate (XP) is an original effective antioxidant that showed decent antioxidant and anti-apoptosis effect before. Thus the therapeutic effect and mechanism of XP in preventing CI-AKI in the short and long term were investigated in this research. Renal function and histological grade were evaluated to determine the severity of renal injury. Kidney samples were then collected for the measurement of oxidative stress markers and the detection of apoptosis. Transmission electron microscopy (TEM) and western blot of mitochondrial protein were utilized for the analysis of the mitochondrial conditions. The results demonstrated that the CI-AKI rats caused a significant decrease in renal function accompanied by a remarkable increase in Malondialdehyde (MDA), bax, caspase-3, cytochrome c (Cyt C) level, TdT-mediated dUTP nick end labeling (TUNEL) positive apoptotic cells, and damaged mitochondria, while a decline in antioxidase activities and mitochondrial superoxide dismutase 2 (SOD2) expression compared with the control rats. However, when XP (50 or 100 or 200 mg/kg/day) was given orally for consecutive 7 days before CI-AKI modeling, XP (200 mg/kg) showed a better capability to restore renal dysfunction, histopathological appearance, the level of apoptosis, mitochondrial damage, oxidative stress, and fibrosis generation without interference in computed tomographic imaging. Our study indicated that antioxidant XP played a nephroprotective role probably via antiapoptotic and antioxidant mechanisms. Besides, XP may regulate the mitochondria pathway via decreasing the ratio of bax/bcl-2, inhibiting caspase-3 expression, cytochrome c release, and superoxide dismutase 2 activity. Overall, XP as a high-efficient antioxidant may have the potentials to prevent CI-AKI.

scholarly journals Human amniotic epithelial cells ameliorate kidney damage in ischemia-reperfusion mouse model of acute kidney injury

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Yifei Ren ◽  
Ying Chen ◽  
Xizi Zheng ◽  
Hui Wang ◽  
Xin Kang ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Kidney Injury ◽  
Renal Function ◽  
Mouse Model ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Mouse Bone Marrow ◽  
Tissue Integration

Abstract Background Acute kidney injury (AKI) is a common clinical disease with complex pathophysiology and limited therapeutic choices. This prompts the need for novel therapy targeting multiple aspects of this disease. Human amnion epithelial cell (hAEC) is an ideal stem cell source. Increasing evidence suggests that exosomes may act as critical cell–cell communicators. Accordingly, we assessed the therapeutic potential of hAECs and their derived exosomes (hAECs-EXO) in ischemia reperfusion mouse model of AKI and explored the underlying mechanisms. Methods The hAECs were primary cultured, and hAECs-EXO were isolated and characterized. An ischemic-reperfusion injury-induced AKI (IRI-AKI) mouse model was established to mimic clinical ischemic kidney injury with different disease severity. Mouse blood creatinine level was used to assess renal function, and kidney specimens were processed to detect cell proliferation, apoptosis, and capillary density. Macrophage infiltration was analyzed by flow cytometry. hAEC-derived exosomes (hAECs-EXO) were used to treat hypoxia-reoxygenation (H/R) injured HK-2 cells and mouse bone marrow-derived macrophages to evaluate their protective effect in vitro. Furthermore, hAECs-EXO were subjected to liquid chromatography-tandem mass spectrometry for proteomic profiling. Results We found that systematically administered hAECs could improve mortality and renal function in IRI-AKI mice, decrease the number of apoptotic cells, prevent peritubular capillary loss, and modulate kidney local immune response. However, hAECs showed very low kidney tissue integration. Exosomes isolated from hAECs recapitulated the renal protective effects of their source cells. In vitro, hAECs-EXO protected HK-2 cells from H/R injury-induced apoptosis and promoted bone marrow-derived macrophage polarization toward M2 phenotype. Proteomic analysis on hAECs-EXO revealed proteins involved in extracellular matrix organization, growth factor signaling pathways, cytokine production, and immunomodulation. These findings demonstrated that paracrine of exosomes might be the key mechanism of hAECs in alleviating renal ischemia reperfusion injury. Conclusions We reported hAECs could improve survival and ameliorate renal injury in mice with IRI-AKI. The anti-apoptotic, pro-angiogenetic, and immunomodulatory capabilities of hAECs are at least partially, through paracrine pathways. hAECs-EXO might be a promising clinical therapeutic tool, overcoming the weaknesses and risks associated with the use of native stem cells, for patients with AKI.

scholarly journals Calreticulin Binds to Fas Ligand and Inhibits Neuronal Cell Apoptosis Induced by Ischemia-Reperfusion Injury

2015 ◽  
Vol 2015 ◽  
pp. 1-8 ◽  
Author(s):  
Beilei Chen ◽  
Zhengzheng Wu ◽  
Jun Xu ◽  
Yun Xu
Keyword(s):  
Reperfusion Injury ◽  
Cell Apoptosis ◽  
Caspase 3 ◽  
Fas Ligand ◽  
Ischemia Reperfusion Injury ◽  
Early Stage ◽  
Neuroprotective Effect ◽  
Ischemia Reperfusion ◽  
Neuronal Cell ◽  
Caspase 8

Background. Calreticulin (CRT) can bind to Fas ligand (FasL) and inhibit Fas/FasL-mediated apoptosis of Jurkat T cells. However, its effect on neuronal cell apoptosis has not been investigated.Purpose. We aimed to evaluate the neuroprotective effect of CRT following ischemia-reperfusion injury (IRI).Methods. Mice underwent middle cerebral artery occlusion (MCAO) and SH-SY5Y cells subjected to oxygen glucose deprivation (OGD) were used as models for IRI. The CRT protein level was detected by Western blotting, and mRNA expression of CRT, caspase-3, and caspase-8 was measured by real-time PCR. Immunofluorescence was used to assess the localization of CRT and FasL. The interaction of CRT with FasL was verified by coimmunoprecipitation. SH-SY5Y cell viability was determined by MTT assay, and cell apoptosis was assessed by flow cytometry. The measurement of caspase-8 and caspase-3 activity was carried out using caspase activity assay kits.Results. After IRI, CRT was upregulated on the neuron surface and bound to FasL, leading to increased viability of OGD-exposed SH-SY5Y cells and decreased activity of caspase-8 and caspase-3.Conclusions. This study for the first time revealed that increased CRT inhibited Fas/FasL-mediated neuronal cell apoptosis during the early stage of ischemic stroke, suggesting it to be a potential protector activated soon after IRI.

scholarly journals The Restoration of Vitamin D Levels Slows the Progression of Renal Ischemic Injury in Rats Previously Deficient in Vitamin D

2021 ◽  
Vol 8 ◽  
Author(s):  
Michele Santiago dos Santos ◽  
Daniele Canale ◽  
Desiree Rita Denelle Bernardo ◽  
Maria Heloisa Massola Shimizu ◽  
Antonio Carlos Seguro ◽  
...  
Keyword(s):  
Vitamin D ◽  
Renal Function ◽  
Renal Disease ◽  
Disease Progression ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Public Health Problem ◽  
Standard Diet ◽  
Renal Disease Progression ◽  
Vitamin D Levels

Chronic kidney disease (CKD) remains a global public health problem. The initial damage after ischemia/reperfusion (I/R) injury plays an important role in the pathogenesis of acute kidney injury (AKI) and predisposition to CKD. Several studies have been showing that nontraditional risk factors such as AKI and hypovitaminosis D could also be involved in CKD progression. Vitamin D deficiency (VDD) is associated with hemodynamic changes, activation of inflammatory pathways and renal disease progression (RDP) following I/R-AKI. Strategies for prevention and/or slowing RDP have been determined and the sufficiency of vitamin D has been emerging as a renoprotective factor in many diseases. Therefore, we investigated the effect of the restoration of vitamin D levels in the progression of I/R injury (IRI) in rats previously deficient in vitamin D. On day 30, male Wistar rats were submitted to bilateral 45 min IRI and divided into three groups: IRI, standard diet for 120 days; VDD+IRI, vitamin D-free diet for 120 days; and VDD+IRI+R, vitamin D-free diet in the first 30 days and just after I/R, we reintroduced the standard diet in the last 90 days. After the 120-day protocol, VDD+IRI+R rats presented an improvement in the renal function and renal protein handling followed by a smaller fractional interstitial area. Furthermore, those animals exhibited a reestablishment regarding the hemodynamic parameters and plasma levels of aldosterone, urea and PTH. In addition, the restoration of vitamin D levels reestablished the amount of MCP1 and the renal expressions of CD68+ and CD3+ cells in the VDD+IRI+R rats. Also, VDD+IRI+R rats showed a restoration regarding the amount of collagen type III and renal expressions of fibronectin, vimentin and α-SMA. Such changes were also accompanied by a reestablishment on the renal expression of VDR, Klotho, JG12, and TGF-β1. Our findings indicate that the restoration of vitamin D levels not only improved the renal function and hemodynamics but also reduced the inflammation and fibrosis lesions observed in I/R-AKI associated with VDD. Thus, monitoring of vitamin D status as well as its replacement in the early stages of kidney injury may be a therapeutic alternative in the mitigation of renal disease progression.

scholarly journals Human amniotic epithelial cells improve kidney repair in ischemia-reperfusion mouse model of acute kidney injury

2020 ◽  
Author(s):  
Yifei Ren ◽  
Ying Chen ◽  
Xizi Zheng ◽  
Hui Wang ◽  
Xin Kang ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Kidney Injury ◽  
Renal Function ◽  
Epithelial Cells ◽  
Mouse Model ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Mouse Bone Marrow ◽  
Tissue Integration

Abstract Background: Acute kidney injury (AKI) is a common clinical disease with complex pathophysiology and very limited therapeutic choices. This prompts the need for novel therapy targeting multiple aspects of this disease. Human amnion epithelial cells (hAECs) are ideal alternative stem cell source for regenerative medicine. Increasing evidence suggests that hAEC-derived exosomes (hAECs-EXO) may act as novel cell–cell communicators. Accordingly, we assessed the therapeutic potential of hAECs in ischemia reperfusion mouse model of AKI and explored the underlying mechanisms.Methods: The hAECs were primary cultured and hAECs-EXO were isolated and characterized. An ischemic renal injury mouse model was established to mimic different severity of the kidney injury. Mouse blood creatinine level was used to assess renal function and kidney specimens were processed to detect cell proliferation, apoptosis and angiogenesis. Immune cells infiltration was analyzed by flow cytometry. hAECs-EXO was used to treat hypoxia-reoxygenation (H/R) injured HK2 cells and mouse bone marrow-derived macrophages to evaluate their protective effect in vitro. Furthermore, hAEC exosomes were subjected to liquid chromatography-tandem mass spectrometry for proteomic profiling. Results: We found that systematically administered hAECs could improve mortality and renal function in IRI mice; decrease the number of apoptotic cells; promote peritubular capillary regeneration and modulate kidney local immune response. However, hAECs showed very low kidney tissue integration. Exosomes isolated from hAECs recapitulated the renal protective effects of their parent cells. In vitro, hAECs-EXO protected HK-2 cells from H/R injury-induced apoptosis and promoted bone marrow-derived macrophage polarization toward M2 phenotype. Proteomic analysis on hAECs-EXO revealed proteins involved in extracellular matrix organization, growth factor signaling pathways, cytokine production and immunomodulation. These findings demonstrated that paracrine of exosomes might be a key mechanism by hAECs mediating kidney functional recovery in AKI.Conclusions: We first reported hAECs could improve mortality and renal repair in mice with ischemia-reperfusion injury. The anti-apoptotic, pro-angiogenetic, and immunomodulatory capabilities of hAECs at least partially, through paracrine pathways. The renoprotective effects of hAECs-EXO might be a promising clinical therapeutic tool, overcoming the weaknesses and risks associated with the use of native stem cells for patients with AKI.

Paricalcitol pretreatment attenuates renal ischemia/reperfusion injury by inhibiting p38 MAPK and activating PI3K/Akt signaling pathways

2019 ◽  
Vol 44 (4) ◽  
pp. 452-461
Author(s):  
Zahide Cavdar ◽  
Cemre Ural ◽  
Ayse Kocak ◽  
Sevki Arslan ◽  
Sibel Ersan ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
P38 Mapk ◽  
Caspase 3 ◽  
Ischemia Reperfusion ◽  
Akt Signaling ◽  
Albino Rats ◽  
Sod Activity ◽  
Interstitial Inflammation ◽  
Tnf Α ◽  
Active Caspase

Abstract Objective This study aimed to investigate the renoprotective effects of paricalcitol, a synhetic vitamin D analog, through its possible roles on p38 MAPK and PI3K/Akt signaling pathways to prevent oxidative stress, inflammation and apoptosis during renal I/R. Materials and methods Total 20 kidney tissues of sham (n = 6), subjected to renal I/R bilaterally for 45 min ischemia followed by 24 h reperfusion (n = 7) and paricalcitol (0.3 μg/kg, ip) pretreated Wistar albino rats (n =7) were used in this study. Interstitial inflammation and active caspase-3 expression were evaluated histologically. TNF-α, IL-1β, kidney injury molecule-1 (KIM-1), MDA and SOD activity in kidneys were analysed biochemically. Furthermore, activation of p38 MAPK, PI3K/Akt signaling pathways and NFκB p65 were evaluated by western blot. Results Paricalcitol pretreatment significantly reduced interstitial inflammation during renal I/R, which was consistent with decreased tumor TNF-α, IL-1β, active caspase-3 and KIM-1 expression. Paricalcitol also reduced MDA level and attenuated the reduction of SOD activity in the kidney during I/R. Moreover, paricalcitol could suppress the p38 MAPK and NFκB p65, and also activate PI3K/Akt signaling pathway during renal I/R. Conclusion All these findings indicate that paricalcitol may be an effective practical strategy to prevent renal I/R injury.

l-NIL prevents renal microvascular hypoxia and increase of renal oxygen consumption after ischemia-reperfusion in rats

2009 ◽  
Vol 296 (5) ◽  
pp. F1109-F1117 ◽  
Author(s):  
Matthieu Legrand ◽  
Emre Almac ◽  
Egbert G. Mik ◽  
Tanja Johannes ◽  
Aslı Kandil ◽  
...  
Keyword(s):  
Renal Function ◽  
Oxygen Consumption ◽  
Oxygen Supply ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
No Synthase ◽  
Metabolic Efficiency ◽  
Sprague Dawley ◽  
Renal Oxygen Consumption ◽  
Renal Oxygen

Even though renal hypoxia is believed to play a pivotal role in the development of acute kidney injury, no study has specifically addressed the alterations in renal oxygenation in the early onset of renal ischemia-reperfusion (I/R). Renal oxygenation depends on a balance between oxygen supply and consumption, with the nitric oxide (NO) as a major regulator of microvascular oxygen supply and oxygen consumption. The aim of this study was to investigate whether I/R induces inducible NO synthase (iNOS)-dependent early changes in renal oxygenation and the potential benefit of iNOS inhibitors on such alterations. Anesthetized Sprague-Dawley rats underwent a 30-min suprarenal aortic clamping with or without either the nonselective NO synthase inhibitor Nω-nitro-l-arginine methyl ester (l-NAME) or the selective iNOS inhibitor l- N6-(1-iminoethyl)lysine hydrochloride (l-NIL). Cortical (CμPo2) and outer medullary (MμPo2) microvascular oxygen pressure (μPo2), renal oxygen delivery (Do2ren), renal oxygen consumption (V̇o2ren), and renal oxygen extraction (O2ER) were measured by oxygen-dependent quenching phosphorescence techniques throughout 2 h of reperfusion. During reperfusion renal arterial resistance and oxygen shunting increased, whereas renal blood flow, CμPo2, and MμPo2 (−70, −42, and −42%, respectively, P < 0.05), V̇o2ren, and Do2ren (−70%, P < 0.0001, and −28%, P < 0.05) dropped. Whereas l-NAME further decreased Do2ren, V̇o2ren, CμPo2, and MμPo2 and deteriorated renal function, l-NIL partially prevented the drop of Do2ren and μPo2, increased O2ER, restored V̇o2ren and metabolic efficiency, and prevented deterioration of renal function. Our results demonstrate that renal I/R induces early iNOS-dependent microvascular hypoxia in disrupting the balance between microvascular oxygen supply and V̇o2ren, whereas endothelial NO synthase activity is compulsory for the maintenance of this balance. l-NIL can prevent ischemic-induced renal microvascular hypoxia.

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