Bone marrow mononuclear cells reduce myocardial reperfusion injury by activating the PI3K/Akt survival pathway.

OBJECTIVE: Adult bone marrow mononuclear cells (BMMNCs) can restore cardiac function following myocardial necrosis. Protocols used to date have administered cells relatively late after ischaemia/reperfusion injury, but there is the opportunity with elective procedures to infuse cells shortly after restoration of blood flow, for example after angioplasty. Our aim was therefore to try and quantify protection from myocardial injury by early infusion of BMMNCs in a rat ischaemia reperfusion (I/R) model. METHODS AND RESULTS: Male Wistar rats underwent 25 min of ischaemia followed by 2 h reperfusion of the left anterior descending coronary artery. Ten million BMMNCs were injected i.v. at reperfusion. We found BMMNCs caused a significant reduction in infarct size at 2 h when assessed by staining the area at risk with p-nitro blue tetrazolium (42% reduction, P<0.01). Apoptosis and necrosis of isolated cardiomyocytes was significantly reduced in the area at risk. Functional assessment at 7 days using echocardiography and left ventricular catheterisation showed improved systolic and diastolic function in the BMMNC treatment group (LVEF: BMMNC 71 ± 3% vs. PBS 48 ± 4%, P<0.0001). In functional studies BMMNC injected animals showed increased activation of Akt, inhibition of GSK-3ß, amelioration of p38 MAP kinase phosphorylation and NF-κB activity compared to control myocardium. Inhibition of PI3K with LY294002 abolished all beneficial effects of BMMNC treatment. Proteomic analysis also demonstrated that BMMNC treatment induced alterations in proteins within known cardioprotective pathways, e.g., heat shock proteins, stress-70 protein as well as the chaperone protein 14-3-3 epsilon. CONCLUSIONS: Early BMMNC injection during reperfusion preserves the myocardium, with evidence of reduced apoptosis, necrosis, and activation of survival pathways.

Generation of endogenous hydrogen sulfide by cystathionine gamma-lyase limits renal ischemia/reperfusion injury and dysfunction.

The generation of endogenous hydrogen sulfide may either limit or contribute to the degree of tissue injury caused by ischemia/reperfusion. A total of 74 male Wistar rats were used to investigate the effects of endogenous and exogenous hydrogen sulfide in renal ischemia/reperfusion. Administration of the irreversible cystathionine gamma-lyase (CSE) inhibitor, dL-propargylglycine, prevented the recovery of renal function after 45 min ischemia and 72 h reperfusion. The hydrogen sulfide donor sodium hydrosulfide attenuated the (renal, tubular, and glomerular) dysfunction and injury caused by 45 min ischemia and 6 h reperfusion. Western blot analysis of kidneys taken at 30 min reperfusion showed that sodium hydrosulfide significantly attenuated phosphorylation of mitogen-activated protein kinases (p-38, c-JUN N-terminal protein kinase 1/2, and extracellular signal-regulated kinase 1/2) and activation of nuclear factor-kappaB. At 6 h reperfusion, sodium hydrosulfide significantly attenuated the histological score for acute tubular necrosis, the activation of caspase-3 and Bid, the decline in the expression of anti-apoptotic Bcl-2, and the expression of nuclear factor-kappaB-dependent proteins (inducible nitric oxide synthase, cyclo-oxygenase-2, and intercellular adhesion molecule-1). These findings suggest that (1) the synthesis of endogenous hydrogen sulfide by CSE is essential to protect the kidney against ischemia/reperfusion injury and dysfunction and aids in the recovery of renal function following ischemia/reperfusion, (2) hydrogen sulfide generated by sodium hydrosulfide reduces ischemia/reperfusion injury and dysfunction, and morphological changes of the kidney, and (3) the observed protective effects of hydrogen sulfide are due to both anti-apoptotic and anti-inflammatory effects.

Renal artery stenosis in chronic renal failure: caution is advised for percutaneous revascularization.

INTRODUCTION: Percutaneous intervention for renal artery stenosis may lead to acute deterioration of renal function and, consequently, of a patient's well-being. The purpose of this study was to determine whether selection by indication for renal artery stenosis was predictive of outcome. METHODS: All patients who underwent intervention for renal artery stenosis were selected to participate in the study and their indication for intervention was determined. Patient characteristics, i.e., renal function and clearance by modified diet in renal disease (MDRD), blood pressure and its treatment, kidney size, proteinuria, and cardiovascular events, were recorded before intervention, at 1 year, and at the end of follow-up. An intervention was classified as a success, no change, or a failure with respect to the indication for intervention. Successful interventions were compared to failures with respect to indication and patient characteristics. RESULTS: Twenty-four patients were included in the study: 11 for renal failure (RF), 9 for hypertension (HT), and 4 due to flash pulmonary edema (FPE). One patient with RF, four with HT, and one with FPE benefited from intervention. Nine patients with RF and two with HT were classified as failures. Failure was most prevalent in the RF group (p<0.05). Other predictors of failure were older age (p<0.02), worse renal function (p<0.02), smaller kidneys (p<0.03), and previous cardiovascular events (p<0.05). CONCLUSIONS: Renal failure must be considered a contraindication for intervention in renal artery stenosis. Intervention can be considered in FPE and hypertension, provided other predictive factors for failure are absent.

Nitrite-derived nitric oxide protects the rat kidney against ischemia/reperfusion injury in vivo: role for xanthine oxidoreductase.

In normal conditions, nitric oxide (NO) is oxidized to the anion nitrite, but in hypoxia, this nitrite may be reduced back to NO by the nitrite reductase action of deoxygenated hemoglobin, acidic disproportionation, or xanthine oxidoreductase (XOR). Herein, is investigated the effects of topical sodium nitrite administration in a rat model of renal ischemia/reperfusion (I/R) injury. Rats were subjected to 60 min of bilateral renal ischemia and 6 h of reperfusion in the absence or presence of sodium nitrite (30 nmol) administered topically 1 min before reperfusion. Serum creatinine, serum aspartate aminotransferase, creatinine clearance, fractional excretion of Na(+), and plasma nitrite/nitrate concentrations were measured. The nitrite-derived NO-generating capacity of renal tissue was determined under acidic and hypoxic conditions by ozone chemiluminescence in homogenates of kidneys that were subjected to sham, ischemia-only, and I/R conditions. Nitrite significantly attenuated renal dysfunction and injury, an effect that was abolished by previous treatment of rats with the NO scavenger 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazole-1-oxyl-3-oxide (2.5 mumol intravenously 5 min before ischemia and 50 nmol topically 6 min before reperfusion). Renal tissue homogenates produced significant amounts of NO from nitrite, an effect that was attenuated significantly by the xanthine oxidoreductase inhibitor allopurinol. Taken together, these findings demonstrate that topically administered sodium nitrite protects the rat kidney against I/R injury and dysfunction in vivo via the generation, in part, of xanthine oxidoreductase-catalyzed NO production. These observations suggest that nitrite therapy might prove beneficial in protecting kidney function and integrity during periods of I/R such as those encountered in renal transplantation.

Renal artery dissection after blunt abdominal trauma: a rare cause of acute cortical necrosis.

Renal artery injury is an uncommon complication of blunt abdominal trauma. We present a case of a 19-year-old man who developed acute cortical necrosis in a congenital single kidney after a motorcycle accident. On initial presentation, he had signs of splenic injury and required immediate laparotomy and splenectomy. His renal function deteriorated, and he became dialysis dependent. Computed tomography followed by percutaneous angiography showed a dissection of a single renal artery causing the formation of a large pseudoaneurysm. A second angiogram showed an increase in the size of the pseudoaneurysm. We performed a laparotomy and attempted in situ vein graft repair of the renal artery. A wedge biopsy specimen taken at laparotomy revealed acute cortical necrosis, and plain radiographs showed cortical calcification. Renal artery dissection and pseudoaneurysm formation are rare events after blunt trauma. Iatrogenic damage is the most common cause of pseudoaneurysm. Traumatic pseudoaneurysms have a poor prognosis without prompt surgical intervention. Renal arterial damage may occur after blunt trauma, and early imaging and intervention are essential to salvage renal function.