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Both the renin-angiotensin-aldosterone system (RAAS) and hypoxia are vital physiological factors involved in the control of nephrogenesis and vascularization. We investigated the relationship between RAAS and hypoxia in the developing kidney. The expression of VEGF and heme oxygenase (HO)-1 related with the oxygen was analyzed in the enalapril- or spironolactone-treated neonatal rat kidneys. Enalapril (30 mg/kg/d) or spironolactone (200 mg/kg/d) was administered to newborn rat pups for 7 d. The newborn rats were injected i.p. with pimonidazole (200 mg/kg), a marker of severe tissue hypoxia, 1 h before killing. VEGF and HO-1 protein expression was significantly increased by immunoblots and immunohistochemistry in both the enalapril- and spironolactone-treated kidneys, compared with the controls (p < 0.05). HO-1 mRNA expression was increased in the spironolactone-treated group (p < 0.05). The immunoactivity of pimonidazole was not different from that of the controls in the enalapril-treated group, whereas it was increased in the spironolactone-treated group. The results of this study indicate that aldosterone blockade or angiotensin II inhibition in the developing rat kidney up-regulated renal VEGF and HO-1 expression regardless of the hypoxic conditions and may differentially modulate VEGF and HO-1 production.

We evaluated the influence of postnatal early overnutrition on renal pathophysiological changes in aging rats. Three or 10 male pups per mother were assigned to either the small litter (SL) or normal litter (control) groups, respectively, during the first 21 d of life. The effects of early postnatal overnutrition were determined at 12 mo. SL rats weighed more than controls between 4 d and 6 mo of age (P < 0.05). However, between 6 and 12 mo, body weights in both groups were not different. In the SL group, at 12 mo, systolic blood pressure was higher and creatinine clearance was lower than the same in controls (P < 0.05). Numbers of CD68 (ED1)-positive macrophages and apoptotic cells in renal cortex were higher in SL rats (P < 0.05). Furthermore, index scores for glomerulosclerosis and tubulointerstitial fibrosis were higher in the SL group (P < 0.05). Significantly less glomeruli per section area were found in aging SL rats (P < 0.05). Immunoblotting and immunohistochemistry showed decreased intrarenal renin expression in SL rats (P < 0.05). Early postnatal overnutrition can potentiate structural and functional abnormalities in the aging kidney and can lead to systolic hypertension with reduced intrarenal renin activity.

We investigated whether genetic polymorphisms of vascular endothelial growth factor (VEGF) and transforming growth factor-beta1 (TGF-beta1), potential candidate genes in the pathogenesis of urinary tract infection (UTI) and vesicoureteral reflux (VUR), are associated with the susceptibility to UTI and VUR, and renal scarring. We recruited 89 controls and 86 UTI and 58 VUR children. The UTI group was subdivided into two groups according to renal scarring. Two polymorphisms of VEGF and three of TGF-beta1 genes were investigated by using PCR-restriction fragment length polymorphism analysis. In both UTI and VUR groups, there was an increase in frequency of the VEGF -460 CC (control, 4.3; UTI, 15.9; VUR, 17.8%; p0.05), TGF-beta1 -509 CC (control, 8.7; UTI, 34.6; VUR, 35.1%; p0.001), and TGF-beta1 -800 GG genotypes (control, 19.1; UTI, 40.5; VUR, 40.4%; p0.05). An increase in the TGF-beta1 +869 CC (scar-positive, 35.4; scar-negative, 10.3%; p0.05) and a decrease in the +869 TC genotype (scar-positive, 29.2; scar-negative, 55.2%; p0.05) were observed in the scar-positive subjects. There were no differences in +405 VEGF genotype frequencies. The VEGF T-460C and the TGF-beta1 C-509T, G-800A, and T869C polymorphisms could be genetic markers of the process of UTI and VUR.

Among the mitogen-activated protein kinase (MAPK) family members, extracellular signal-regulated kinase (ERK) promotes cell proliferation or differentiation, whereas c-jun N terminal kinase (JNK) and p38 MAPK are thought to inhibit cell growth and induce apoptosis. The MAPK family may plays some role during kidney development, when large-scale proliferation and apoptosis have been observed to occur. Also, in this period, the renin-angiotensin system is markedly activated. We have demonstrated that angiotensin-converting enzyme inhibition in the developing rat kidney increases apoptosis and decreases cell proliferation, which may account for renal growth impairment. The aim of this study, therefore, was to examine the relationship between the MAPK family and renin-angiotensin system during neonatal renal development. Newborn rat pups were treated with enalapril (30 mg . kg(-1) . d(-1)) or normal saline for 7 d. Right kidneys of both groups were selected for immunohistochemical stains of MAPKs and activating transcription factor-2 (ATF-2), and left kidneys were selected for reverse transcriptase-PCR and immunoblot analysis of MAPKs, phospho-MAPKs, and ATF-2. To determine whether apoptosis is involved in the same tubules that highly expressed JNK and p38, we performed terminal deoxynucleotide transferase-mediated nick-end labeling stain for apoptotic cells and immunohistochemical stains for JNK-2, p38, and ATF-2 expression in the serial sections from the same kidney of the enalapril-treated group. In the enalapril-treated group, JNK-2, p38, phospho-JNK-2, phospho-p38, and ATF-2 protein expressions were significantly increased, and their immunoactivities were strongly detected in the proximal tubular epithelial cells in the cortex, compared with the control group. Especially JNK-2 and p38 expressions were highly activated and were spatially in accordance with the occurrence of apoptosis. ERK1/2 and phospho-ERK expressions were not changed by enalapril. These results suggest that the expressions of the MAPK family are modulated by angiotensin-converting enzyme inhibition in the developing kidney. JNK and p38 may be implicated to participate in angiotensin II-related intracellular signaling pathways of renal apoptosis in the developing kidney.

To assess predisposing factors of coronary artery abnormalities(CAA) in Kawasaki disease, clinical records of patients with a discharge diagnosis of Kawasaki disease at Korea University Medical Center from 1999 to 2001 were reviewed. A total of 99 patients were diagnosed and 11 patients developed CAA (11%). Variable factors including clinical manifestations, laboratory measurements, treatment and its responses were evaluated to predict CAA. Sixty five patients met complete American Heart Association (AHA) criteria (typical KD) whereas 34 patients did not (atypical KD). CAA were developed in 5 of typical KD compared to 6 of atypical KD (7.7% vs 17.6%). Intravenous immune globulin (IVIG) were administrated in 91 patients and 9 of them developed CAA compared to 2 of 8 who did not received IVIG (10% vs 25%). When the IVIG responsiveness was defined by the presence or absence of defervescence within 5 days after IVIG therapy, 75 were IVIG-responsive and 16 were not. Six in the IVIG-responsive group developed CAA compared to 3 in the IVIG-non-responsive group (8% vs 19%). A total of 62 patients were male and 8 of them developed CAA compared to 3 of 34 female patients (13% vs 8%). Total duration of fever, a duration of fever before the initiation of IVIG and the level of C-reactive protein (CRP) at onset were significantly higher (p=0.0018, p=0.0095, p=0.002) and the hemoglobin level at onset was significantly lower in CAA group (p=0.0009). Conclusively, predisposing factors of CAA in Kawasaki disease are male gender, atypical manifestations, no IVIG therapy, no IVIG-responsiveness, longer duration of total fever, longer duration of fever before the initiation of IVIG, the higher level of CRP and the lower level of hemoglobin at onset.

To assess the overall outcome of Kawasaki disease, patients with a discharge diagnosis of Kawasaki disease at Korea University Medical Center from 1999 to 2001 were retrospectively evaluated. A total of 99 patients were diagnosed. The American Heart Association (AHA) criteria were met in 65 patients (66%) and 63 of them received intravenous immune globulin (IVIG, 2g/kg). Fifty patients responded afebrile within 5 days (IVIG-responsive) and 13 patients did not (IVIG-non-responsive). Within 2 months, 2 patients in the IVIG-responsive group developed coronary abnormalities compared to 3 patients in the IVIG-non-responsive group (4% vs 23%). None of whom met AHA criteria and did not received IVIG were febrile more than 5 days nor developed coronary abnormalities. In 34 patients who did not meet complete AHA criteria, 28 patients received IVIG and 25 patients were IVIG-responsive. Coronary abnormalities were developed in 4 in the IVIG-responsive group compared to none in the IVIG-non-responsive group (16% vs 0%). All 6 patients who did not meet complete AHA criteria and did not received IVIG were febrile more than 5 days and 2 of them developed coronary abnormalities. Taken together, coronary abnormalities were developed in 9 patients of 91 who were treated with IVIG compared to 2 patients of 8 who were not treated with IVIG (10% vs 25%). In conclusion coronary abnormalities were developed in 11 of 99 patients with Kawasaki disease (11%).