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.
Our study results demonstrated that n-3 PUFA prevented renal progression with attenuation of SREBP-1 and reduction of triglyceride in the diabetic kidney. This suggests that the regulation of dyslipidemic signals in the kidney could be a possible mechanism by which PUFA preserves renal function in the diabetic condition.
Low-grade albuminuria has been proposed as a cardiovascular risk factor that is below the conventional cut-off point for microalbuminuria, which has been previously identified as a marker for cardiovascular disease and chronic kidney disease (CKD). Metabolic syndrome has also been shown to be related with microalbuminuria and CKD. We assessed the relationship among low-grade albuminuria, CKD and metabolic syndrome among 5998 non-diabetic subjects. The subjects were divided into six groups: subjects with urine albumin-to-creatinine ratio (UACR) o30 mg g À1 were divided into five groups in accordance with their UACR values, and subjects with 30pUACR o300 mg g À1 were allocated to the microalbuminuria group. The prevalence of CKD increased in parallel with increasing UACR values and greater numbers of metabolic syndrome characteristics, which were in turn associated with a reduced UACR cut-off point for an increased prevalence of CKD. Among the subjects with metabolic syndrome, UACR values above 10.2 mg g À1 were related to increased CKD prevalence (odds ratio (OR): 2.63, 95% confidence interval (CI) 1.11-6.24), as were values of 30 mg g À1 among those with 1 or 2 components of metabolic syndrome (OR: 2.98, 95% CI 1.83-4.83); elevated UACR was not observed to increase the risk of CKD in subjects who had no components of metabolic syndrome. The cut-off point varied in subjects with various cardiovascular risk profiles such as serum uric acid level, gender or hypertension. Very low levels of albuminuria were associated with increased CKD prevalence. The UACR cut-off point for increased CKD risk varied according to the risk profile, including the number of metabolic syndrome components.
Hypoxia-inducible factor (HIF) is a transcription factor that regulates cellular hypoxic responses. Despite the therapeutic benefits of cyclosporine A (CsA) in organ transplantation, its clinical use is limited due to chronic nephropathy. We investigated whether HIF activation by cobalt could improve CsA-induced nephropathy, and investigated the related mechanism. In animal experiments, rats were kept on a 0.05% low-salt diet and administered CsA subcutaneously for 28 days (15 mg/kg/day). They also received cobalt (10 mg/kg/day) during the entire experimental period. The administration of cobalt significantly increased HIF-1α expression in the kidney. The increased expression of HIF-1α ameliorated CsA-induced afferent arteriolopathy and tubulointerstitial injury in the kidney. Cobalt significantly reduced the infiltration of macrophages/monocytes into the renal tubulointerstitium. In addition, HIF activation by cobalt reduced the number of CsA-induced apoptotic cells in the kidney. Subsequently, HK-2 human renal tubular epithelial cells were used for in vitro experiments. They were pre-treated with 150 µM of cobalt to activate HIF, and then exposed to 10 µM CsA. HIF activation by cobalt decreased the CsA-induced apoptosis in HK-2 cells, as judged by the decreases in the number of apoptotic cells, pro-apoptotic caspase-3 activity, and the expression level of cleaved caspase-3, together with the increase in the expression of anti-apoptotic bcl-2. Cobalt pretreatment also reduced the CsA-induced phosphorylation of NF-κB and the CsA-induced expression of vimentin and α-smooth muscle actin, suggesting the attenuation of inflammation and fibrosis. In conclusion, the activation of HIF by cobalt may ameliorate the CsA-induced nephropathy by inhibiting apoptosis, inflammation, and fibrosis.
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