These results suggest that macrophages are an important mediator in the initiation period of ischaemia/reperfusion injury and strategies that limit initial macrophage infiltration or activation can be useful in the treatment of acute renal failure.

These data provide evidence that ERK1/2 pathway functions as an upstream signal for TNF-alpha-mediated inflammation and caspase 3-mediated apoptosis in cisplatin-induced ARF in mice and suggest that ERK1/2 can be a novel therapeutic target in cisplatin nephrotoxicity.

Background. Ischaemia/reperfusion is a major cause of acute kidney injury and can result in poor long-term graft function. Although most of the patients with acute kidney injury recover their renal function, significant portion of patients suffer from progressive deterioration of renal function. A persistent inflammatory response might be associated with long-term changes following acute ischaemia/reperfusion. Macrophages are known to infiltrate into tubulointersitium in animal models of chronic kidney disease. However, the role of macrophages in long-term changes after ischaemia/reperfusion remains unknown. We aimed to investigate the role of macrophages on the development of tubulointerstitial fibrosis and functional impairment following acute ischaemia/reperfusion injury by depleting macrophages with liposome clodronate. Methods. Male Sprague-Dawley rats underwent right nephrectomy and clamping of left renal vascular pedicle or sham operation. Liposome clodronate or phosphate buffered saline was administered for 8 weeks. Biochemical and histological renal damage and gene expression of various cytokines were assessed at 4 and 8 weeks after ischaemia/reperfusion. Results. Ischaemic/reperfusion injury resulted in persistent inflammation and tubulointerstital fibrosis with decreased creatinine clearance and increased urinary albumin excretion at 4 and 8 weeks. Macrophage depletion attenuated those changes. This beneficial effect was accompanied with a decrease in gene expression of inflammatory and profibrotic cytokines. Conclusions. These results suggest that macrophages play an important role in mediating persistent inflammation and fibrosis after ischaemia/reperfusion leading to a development of chronic kidney disease. Strategies targeting macrophage infiltration or activation can be useful in the prevention of development of chronic kidney disease following ischaemic injury.

Chronic kidney disease (CKD) is a worldwide problem. This study was designed to survey the prevalence and risk factors for CKD in Korea. The 2,356 subjects were selected in proportion to age, gender, and city. Subjects 35 yr of age or older were selected from 7 cities. Estimated glomerular filtration rate (eGFR) was calculated using the Modification of Diet in Renal Disease (MDRD) Study equation, with albuminuria defined as a urine albumin to creatinine ratio of 30 mg/g or more. The overall prevalence of CKD was 13.7%. The prevalences of CKD according to stage were 2.0% stage 1, 6.7% stage 2, 4.8% stage 3, 0.2% stage 4, and 0.0% stage 5. The prevalences of microalbuminuria and macroalbuminuria were 8.6% and 1.6%, respectively. The prevalence of eGFR less than 60 mL/min/1.73 m2 was 5.0%. Age, body mass index (BMI), hypertension, diabetes mellitus, systolic blood pressure (SBP), diastolic blood pressure (DBP), and fasting blood glucose were independent factors related to the presence of CKD. In conclusions, Korea, in which the prevalence of CKD is increasing, should prepare a policy for early detection and appropriate treatment of CKD. The present data will be helpful in taking those actions.

Role of vascular endothelial growth factor in diabetic nephrop-tractive candidate in this regard because VEGF markathy.edly increases vascular permeability and potently stimu-Background. Vascular endothelial growth factor (VEGF) is lates the vascular endothelial cell to divide [2,3]. Its a potent cytokine that is considered to be an important mediapathogenic role in diabetic retinopathy is widely accepted, tor in the pathogenesis of endothelial dysfunction in diabetes. and it predominantly mediates the neoangiogenesis asso-Methods. This study investigates the effect of high glucose on the signaling and production of VEGF in rat mesangial ciated with proliferative retinopathy [4, 5]. Endothelial cells in culture and measures the urinary VEGF level in patients dysfunction, which is also associated with diabetic newith different stages of diabetic nephropathy. To elucidate the phropathy, may play a pathogenic role in the developrole of VEGF in vivo further, expression of VEGF in control ment of diabetic renal disease [6, 7], but this remains and diabetic kidneys was examined using immunohistochemspeculative at this time. istry.Results. A high ambient glucose concentration in the cultureIn this study, we examined the effects of a high-glucose medium increased VEGF mRNA expression and protein proconcentration in culture media on VEGF mRNA expresduction within 3 h in a concentration-dependent manner. A sion and protein production in rat mesangial cells. We protein kinase C (PKC) inhibitor and PKC down-regulation also established whether VEGF production depends on inhibited glucose-induced increases in VEGF production. Urinary excretion of VEGF significantly increased according to the protein kinase C (PKC) pathway. In a human study, the degree of proteinuria in patients with diabetes. A weak we determined the plasma and urine concentrations of but significant correlation was found between urinary VEGF VEGF and searched for any relationship between these excretion and the levels of serum creatinine, creatinine clearvalues and the severity of diabetic nephropathy. To unance, microalbuminuria, and proteinuria. Immunohistochemisderstand the role of VEGF in diabetic kidney disease try revealed marked differences in the extent of mesangial VEGF staining between diabetic and control kidneys. Profurther, renal biopsies from 20 patients with noninsulinnounced up-regulation of VEGF was observed in the glomerudependent diabetes mellitus (NIDDM) and 3 patients lar epithelial cell in the early phase of diabetic kidney disease,with renal cell carcinoma undergoing nephrectomy were whereas widespread expression of VEGF was found in the stained with a rabbit anti-VEGF antibody.tubular segments, especially the proximal segment, in advanced diabetic nephropathy.Conclusions. These results suggest that VEGF may play a METHODSrole in the pathogenesis of diabetic nephropathy. Rat mesangial cell cultureGlomeruli were isolated from male Sprague-Dawley Abnormalities in endothelial function, such as inrats weighing an average of 100 g. The kidne...

Background/Aims: Increased susceptibility of the kidney to acute renal failure (ARF) in the setting of sepsis even in the absence of systemic hypotension is well known. In the hypothesis that the proinflammatory cytokines and lipopolysaccharide (LPS) in gram-negative sepsis can directly cause renal tubular cell apoptosis via Fas- and caspase-mediated pathways, we examined apoptosis and Fas, Fas ligand, FADD expression, as well as PARP cleavage in cultured human proximal tubular cells under the cytokine and LPS-stimulated conditions. Methods: HK-2 cell, immortalized human proximal tubular cell lines, were treated with 5 and 30 ng/ml of tumor necrosis factor-α (TNF-α), 5 and 20 ng/ml of interleukin-1β (IL-1β) and 30 ng/ml LPS for 24 h. Fas expression was examined by RT-PCR and Fas ligand, Fas-associated protein with death domain (FADD) and poly ADP ribose polymerase (PARP) cleavage were examined by Western blot analysis. Apoptosis was assessed by flow cytometer using Annexin V-FITC and propidium iodide (PI) staining and also by terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling (TUNEL) methods. Results: Fas mRNA expression (ratio of Fas/L-19) increased in the TNF-α 5, 30 ng/ml and LPS treated group (p < 0.01, p < 0.01, p = 0.02), but there was no difference between the low- and high-dose TNF-α groups. Fas ligand protein expression did not increase in the low-dose TNF-α treated group, but it increased significantly in the high-dose TNF-α treated group (p< 0.01), IL-1β- and LPS-treated groups (p < 0.01, p = 0.01, p < 0.01, p = 0.02). The intracellular adaptor protein, FADD expression also increased significantly in the high-dose TNF-α- and IL-β-treated groups (p = 0.04, p = 0.04), but in the low-dose TNF-α and IL-β treated group, it did not show statistically significant differences. In the LPS group, FADD expression also showed an increased tendency, but it was not statistically significant (p = 0.09). Western blot for PARP, a DNA repair enzyme mainly cleaved by caspase 3, showed increased 89- and 24-kD PARP cleavage products in TNF-α, IL-1β and LPS treated cells. The degree of apoptosis examined by DNA fragmentation and translocation of membrane phosphatidyl serine significantly increased in cytokines and LPS treated groups. Conclusion: These results suggest that Fas- and caspase-mediated apoptosis of tubular cells by inflammatory cytokines and LPS can be one of the possible mechanisms of renal dysfunction in endotoxemia.

Our results suggest that kidney CD11c(+) F4/80(+) dendritic subset might contribute to the recovery process by dynamic phenotypic change from pro-inflammatory to anti-inflammatory with modulation of immune response.

Our results suggest that intestinal dysbiosis-associated gut barrier disruption and aberrant mucosal immunity are important for the systemic inflammation and progressive fibrosis of CKD. Targeting the intestine might provide novel therapeutic opportunities for CKD.