Hypoxia-inducible factor activation protects the kidney from gentamicin-induced acute injury.

Gentamicin nephrotoxicity is one of the most common causes of acute kidney injury (AKI). Hypoxia-inducible factor (HIF) is effective in protecting the kidney from ischemic and toxic injury. Increased expression of HIF-1α mRNA has been reported in rats with gentamicin-induced renal injury. We hypothesizd that we could study the role of HIF in gentamicin-induced AKI by modulating HIF activity. In this study, we investigated whether HIF activation had protective effects on gentamicin-induced renal tubule cell injury. Gentamicin-induced AKI was established in male Sprague-Dawley rats. Cobalt was continuously infused into the rats to activate HIF. HK-2 cells were pre-treated with cobalt or dimethyloxalylglycine (DMOG) to activate HIF and were then exposed to gentamicin. Cobalt or DMOG significantly increased HIF-1α expression in rat kidneys and HK-2 cells. In HK-2 cells, HIF inhibited gentamicin-induced reactive oxygen species (ROS) formation. HIF also protected these cells from apoptosis by reducing caspase-3 activity and the amount of cleaved caspase-3, and -9 proteins. Increased expression of HIF-1α reduced the number of gentamicin-induced apoptotic cells in rat kidneys and HK-2 cells. HIF activation improved the creatinine clearance and proteinuria in gentamicin-induced AKI. HIF activation also ameliorated the extent of histologic injury and reduced macrophage infiltration into the tubulointerstitium. In gentamicin-induced AKI, the activation of HIF by cobalt or DMOG attenuated renal dysfunction, proteinuria, and structural damage through a reduction of oxidative stress, inflammation, and apoptosis in renal tubular epithelial cells.

Activation of hypoxia-inducible factor attenuates renal injury in rat remnant kidney.

BACKGROUND: Chronic hypoxia in the kidney has been suggested as a final common pathway to end-stage renal disease. Hypoxia-inducible factor (HIF) is a transcription factor that regulates cellular hypoxic responses, and it is a promising target with therapeutic potential in various kidney disease models. In this study, we investigated whether HIF activation could attenuate renal injury in the rat remnant kidney model. METHODS: Two weeks after a subtotal nephrectomy, rats received a continuous infusion of dimethyloxalylglycine (DMOG) for 4 weeks to activate HIF. RESULTS: The DMOG infusion halted the progression of proteinuria. A histological evaluation revealed that the glomerulosclerosis and tubulointerstitial injury were significantly decreased by DMOG treatment. DMOG increased renal HIF-1alpha protein. The expression of glucose transporter-1 (GLUT-1) and prolyl hydroxylase 3 (PHD3) and the immunostaining of vascular endothelial growth factor (VEGF) were increased by DMOG. DMOG-treated rats showed less podocyte injury manifested by decreased immunostaining of desmin and the restoration of podoplanin staining. Furthermore, plasma malondialdehyde (MDA), a marker of oxidative stress, showed a tendency to decrease, and the renal expression of catalase, an antioxidant, was significantly increased by DMOG. The DMOG treatment decreased macrophage infiltration and reduced fibrosis, as manifested by decreased type IV collagen and osteopontin expression. CONCLUSIONS: Activation of HIF by DMOG halted the progression of proteinuria and attenuated structural damage by preventing podocyte injury in the remnant kidney model. This renoprotection was accompanied by a reduction of oxidative stress, inflammation and fibrosis.

Prevention of acute kidney injury by erythropoietin in patients undergoing coronary artery bypass grafting: a pilot study.

BACKGROUND/AIMS: Depending on the specific definition, acute kidney injury (AKI) occurs in 7-40% of patients undergoing cardiac surgery. Even small changes in serum creatinine (SCr) levels are associated with increased mortality after cardiac surgery. However, there are no current methods for preventing AKI after cardiac surgery. Erythropoietin (EPO) has been shown to elicit tissue-protective effects in various experimental models. In this pilot trial, we evaluated the effectiveness of EPO in the prevention of AKI after coronary artery bypass grafting (CABG). METHODS: 71 patients scheduled for elective CABG randomly received either 300 U/kg of EPO or saline intravenously before surgery. AKI was defined as a 50% increase in SCr levels over baseline within the first 5 postoperative days. Estimated glomerular filtration rate (eGFR) was calculated from the Cockcroft-Gault equation. RESULTS: Of 71 patients, 13 developed postoperative AKI: 3 of the 36 patients in the EPO group (8%) and 10 of the 35 patients in the placebo group (29%; p = 0.035). The increase in postoperative SCr concentration and the decline in postoperative eGFR were significantly lower in the EPO group than in the placebo group. CONCLUSIONS: In our small, pilot trial, prophylactic administration of EPO prevents AKI and improves postoperative renal function. These data are preliminary and require confirmation in a larger clinical trial.

Cerebral infarction as a complication of nephrotic syndrome: a case report with a review of the literature.

Arterial thrombosis is relatively rare compared with venous thrombosis in nephrotic syndrome. However, the assessment of its pathogenesis and risk factors in individual patient with nephrotic syndrome is necessary to allow appropriate prophylactic management because it is a potentially serious problem. Hereby, with review of the literature, we report a case of a 53 yr-old man with cerebral infarction associated with nephrotic syndrome due to focal segmental glomerulosclerosis during the course of treatments with diuretics and steroid. It reveals that the hypercoagulable state in nephrotic syndrome can be associated with cerebral infarction in adults. Prophylactic anticoagulants can be considered to reduce the risk of serious cerebral infarction in nephrotic patients with risk factors such as severe hypoalbuminemia and on diuretics or steroid treatment, even in young patients regardless of types of underlying glomerular diseases.