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 by cobalt is associated with the attenuation of tissue injury and apoptosis in cyclosporine-induced nephropathy.

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.

Very low-grade albuminuria reflects susceptibility to chronic kidney disease in combination with cardiovascular risk factors.

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) <30 mg g(-1) were divided into five groups in accordance with their UACR values, and subjects with 30

Impact of C-reactive protein and pulse pressure evaluated at the start of peritoneal dialysis on cardiovascular events in the course of treatment with peritoneal dialysis.

BACKGROUND: Despite a reduced number of infectious complications, cardiovascular (CV) mortality remains unchanged in peritoneal dialysis (PD) patients. The aim of this study was to evaluate the effects of high-sensitivity C-reactive protein (hs-CRP) and pulse pressure (PP) at the start of PD on the development of CV events (CVEs) in these patients. METHODS: The study population was comprised of 291 patients that started PD between January 2003 and June 2008 and were treated for more than 6 months. Baseline clinical, biochemical, and echocardiographic data, indices of dialysis adequacy, and peritoneal transport rate were reviewed retrospectively. The clinical outcome was the occurrence of a CVE. RESULTS: Mean duration of follow-up was 28 (range 6 - 70) months. A CVE was observed in 33 patients (11.3%). The 1-, 3-, and 5-year cumulative incidences of CVEs were 4.0%, 13.7%, and 27.5%, respectively. Although multiple variables were correlated with the prevalence of a CVE in the univariate analysis, hs-CRP, PP, and comorbidity remained significant after adjustment: hs-CRP: odds ratio (OR) 4.09 (1.53 - 10.95), p = 0.005; PP: OR 2.79 (1.26 - 6.17), p = 0.012. PP and hs-CRP, which were not intercorrelated in our data, combined adversely to increase the incidence of CVEs. The incidence of CVEs increased with the number of risk factors, which included high hs-CRP, high PP, and the presence of comorbidity (no risk factor, 0%; 1 risk factor, 1.5%; 2 risk factors, 30.8%; 3 risk factors, 53.9%). CONCLUSIONS: Our study suggests that measurements of hs-CRP and PP at the start of PD may be helpful in predicting the development of CVEs in the course of treatment with PD.

Omacor, n-3 polyunsaturated fatty acid, attenuated albuminuria and renal dysfunction with decrease of SREBP-1 expression and triglyceride amount in the kidney of type II diabetic animals.

BACKGROUND: We assumed that n-3 polyunsaturated fatty acid (n-3 PUFA) would attenuate the tissue dyslipidemic condition through suppression of sterol regulatory element-binding protein (SREBP-1) in the kidney and would prevent renal progression in diabetic animals. METHODS: We gavaged Omacor, composed of docosahexaenoic acid and eicosapentaenoic acid, to db/db mice for 2 weeks (0.2 g/100 g/day). We measured the markers of renal function, triglyceride amount and expressions of SREBP-1, liver X-activated receptor alpha (LXRalpha), collagen IV and TGFbeta-1 in kidney lysate, and performed immunohistochemical staining for SREBP-1, desmin and WT-1 in the renal sections. We measured collagen IV in primary mesangial cells cultured with high glucose media (25 mM), both with and without a transient transfection of small interfering RNA (siRNA) SREBP-1. RESULTS: Omacor decreased the concentration of serum free fatty acid, and the amount of renal triglyceride, which was associated with decreased expression of SREBP-1 in the kidney, albuminuria and renal dysfunction in db/db mice. Omacor attenuated the expansion of mesangial matrix and the expression of desmin, preserved the WT-1 positive cells, and inhibited the phosphorylation of nuclear factor kappaB in renal tissue. In mesangial cells cultured in high glucose media, the suppression of SREBP-1 expression decreased the collagen IV in the cells. CONCLUSIONS: 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.