Risk factors for treatment failure of heated humidified high-flow nasal cannula as an initial respiratory support in newborn infants with respiratory distress.

BACKGROUND: Humidified high-flow nasal cannula (HHFNC) has gained popularity because it is easier to use, more comfortable for babies, and advantageous for mother-infant bonding. HHFNC is not inferior to other non-invasive ventilators for preventing adverse outcomes, but more studies are needed to ensure the safe use of HHFNC as an initial respiratory support for newborns. The aim of this study was to investigate risk factors for treatment failure of HHFNC as an initial respiratory support in newborns with respiratory distress after birth. METHODS: We included 97 newborns who required non-invasive respiratory support within 24 h after birth. The success group included 68 infants who were successfully managed only on HHFNC, and 29 infants were the failure group who required other respiratory support because of respiratory acidosis, hypoxia, or apnea. RESULTS: Compared with the success group, the failure group had lower GA, a higher rate of antenatal steroid use, prolonged rupture of membrane, lower pH, higher pCO2 on blood-gas analysis after HHFNC application and higher incidence of respiratory distress syndrome of newborn (RDS). After adjusting for GA, higher FiO2 settings during acidosis, hypercarbia after the application of HHFNC shown on blood-gas analysis and the presence of RDS remained significant. The rate of treatment failure was 16.2% for ≥36 weeks, 19.3% for ≥34 weeks, and 22.1% for ≥33 weeks. CONCLUSION: Treatment failure of HHFNC should be considered a risk for newborns of less than 34 weeks and infants with respiratory distress from RDS. Higher FiO2 settings during HHFNC, and acidosis and hypercarbia after the application of HHFNC shown on blood-gas analysis may help identify high-risk newborns for other non-invasive ventilators or intubation.

Angiotensin inhibition in the developing kidney; tubulointerstitial effect.

BACKGROUND: Renin-angiotensin system (RAS) blockade during nephrogenesis causes a broad range of renal mal-development. Here, we hypothesized that disruption of renal lymphangiogenesis may contribute to tubulointerstitial alterations after RAS blockade during kidney maturation. METHODS: Newborn rat pups were treated with enalapril (30 mg/kg/day) or vehicle for 7 days after birth. Lymphangiogenesis was assessed via immunostaining and/or immunoblots for vascular endothelial growth factor (VEGF)-C, VEGF receptor (VEGFR)-3, Podoplanin, and Ki-67. The intrarenal expression of fibroblast growth factor (FGF)-1, FGF-2, FGF receptor (R)-1, α-smooth muscle actin (α-SMA), and fibroblast-specific protein (FSP)-1 was also determined. Sirius Red staining was performed to evaluate interstitial collagen deposition. RESULTS: On postnatal day 8, renal lymphangiogenesis was disrupted by neonatal enalapril treatment. The expression of podoplanin and Ki-67 decreased in enalapril-treated kidneys. While the expression of VEGF-C was decreased, the levels of VEGFR-3 receptor increased following enalapril treatment. Enalapril treatment also reduced the renal expression of FGF-1, FGF-2, and FGFR-1. Enalapril-treated kidneys exhibited profibrogenic properties with increased expression of α-SMA and FSP-1 and enhanced deposition of interstitial collagen. CONCLUSION: Enalapril treatment during postnatal renal maturation can disrupt renal lymphangiogenesis along with tubulointerstitial changes, which may result in a pro-fibrotic environment in the developing rat kidney.

Capillary rarefaction and altered renal development: the imbalance between pro- and anti-angiogenic factors in response to angiotensin II inhibition in the developing rat kidney.

Proper and timely assembly of the kidney vasculature with their respective nephrons is crucial during normal kidney development. In this study, we investigated the effects of enalapril (angiotensin-converting enzyme inhibitor) on angiogenesis-related gene expression and microvascular endothelium related to glomeular and tubular changes in the neonatal rat kidney. Enalapril-treated rats had higher tubular injury scores and lower glomerular maturity grades than those of untreated rats. In the enalapril-treated group, intrarenal angiopoietin-2, Tie-2, and thrombospondin-1 protein expression increased, whereas intrarenal angiopoietin-1 protein expression decreased. JG12-positive glomerular and peritubular capillary staining was reduced in the enalapril-treated rat kidney. The number of JG12-positive capillary endothelial cells was directly correlated with glomerular maturation grade and was inversely related with the tubular injury. Our findings suggest the imbalance between pro- and anti-angiogenic factors may be implicated in the loss of capillaries in associated with impaired nephrogenesis after angiotensin II blockade in the developing rat kidney.

Genetic Contributions to Childhood Obesity: Association of Candidate Gene Polymorphisms and Overweight/Obesity in Korean Preschool Children.

This study was aimed to investigate the association of candidate gene polymorphisms and obesity or overweight in young Korean children. A total of 190 Korean preschool children (96 control, 48 overweight, and 46 obese children) were genotyped for the angiotensin converting enzyme (ACE) insertion (I)/deletion (D), angiotensin II type 2 receptor (AT2) C3123A, transforming growth factor (TGF)-ß1 T869C, vascular endothelial growth factor (VEGF) T460C, and tumor necrosis factor (TNF)-α G308A polymorphisms. No differences were found among the groups with respect to age, sex, birth weight, blood pressure levels, and serum concentrations of glucose and total cholesterol. Obese children showed a higher incidence of ACE DD genotype and D allelic frequency compared to the controls (odds ratio [OR], 2.7, 95% confidence interval [CI], 1.01-7.21; OR, 2.5, 95% CI, 1.49-4.19; all P < 0.05). The frequency of TC genotype and C allele in the TGF-ß1 T869C polymorphism (OR, 2.08, 95% CI, 1.01-4.27; OR, 1.93, 95% CI, 1.15-3.21) and that in the VEGF T460C polymorphism (OR, 2.5, 95% CI, 1.19-5.28; OR, 2.15, 95% CI, 1.26-3.68) was also higher in obese children than in control subjects (all P < 0.05). Overweight children exhibited a higher frequency of the A allele in the AT2 C3123A polymorphism compared to the controls (OR, 1.72, 95% CI, 1.03-2.88, P < 0.05). There were no differences in the TNF-α G308A polymorphism among the groups. The ACE I/D, AT2 C3123A, TGF-ß1 T869C, and VEGF T460C polymorphisms can affect susceptibility to obesity or overweight in Korean children.

Individualized ibuprofen treatment using serial B-type natriuretic peptide measurement for symptomatic patent ductus arteriosus in very preterm infants.

PURPOSE: Plasma level of B-type natriuretic peptide (BNP), an emerging, sensitive, and specific biomarker of hemodynamically significant patent ductus arteriosus (PDA), rapidly decreases in infants receiving cyclooxygenase inhibitors for ductal closure. We investigated the usefulness of serial BNP measurement as a guide for individual identification of early constrictive responses to ibuprofen in preterm infants with symptomatic PDA (sPDA). METHODS: Before March 2010, the standard course of pharmacological treatment was initiated with indomethacin (or ibuprofen) and routinely followed by 2 additional doses at intervals of 24 hours. After April 2010, individualized pharmacological treatment was used, starting with the first dose of ibuprofen and withholding additional ibuprofen doses if the BNP concentration was <600 pg/mL and clinical symptoms of PDA improved. RESULTS: The BNP-guided group received significantly fewer doses of ibuprofen than the standard group did during the first course of treatment and the entire study period. The need for further doses of cyclooxygenase inhibitors and for surgical ligation was not significantly different between the 2 groups. No significant differences were seen in clinical outcomes and/or complications related to sPDA and/or pharmacological treatment. CONCLUSION: Individualized BNP-guided pharmacological treatment may be used clinically to avoid unnecessary doses of cyclooxygenase inhibitors without increasing the ductal closure failure and the short-term morbidity related to sPDA.

The influencing factors on procalcitonin values in newborns with noninfectious conditions during the first week of life.

PURPOSE: Although procalcitonin (PCT) level is useful for the diagnosis of neonatal sepsis, PCT reliability is inconsistent because of the varied conditions encountered in neonatal intensive care units. This study aimed to investigate PCT levels and factors influencing increased PCT levelin newborns without bacterial infection during the first week of life. METHODS: In newborns hospitalized between March 2013 and October 2015, PCT levels were measured on the first, third, and seventh days after birth. Newborns with proven bacterial (blood culture positive for bacteria) or suspicious infection (presence of C-reactive protein expression or leukocytosis/leukopenia) were excluded. Various neonatal conditions were analyzed to identify the factors influencing increased PCT level. RESULTS: Among 292 newborns with a gestational age of 35.2±3.0 weeks and a birth weight of 2,428±643 g, preterm newborns (n=212) had higher PCT levels than term newborns (n=80). Of the newborns, 7.9% had increased PCT level (23 of 292) on the firstday; 28.3% (81 of 286), on the third day; and 3.3% (7 of 121), on the seventh day after birth. The increased PCT level was significantly associated with prenatal disuse of antibiotics (P=0.004) and surfactant administration (P<0.001) on the first day after birth, postnatal use of antibiotics (P=0.001) and ventilator application (P=0.001) on the third day after birth, and very low birth weight (P=0.042) on the seventh day after birth. CONCLUSION: In newborns without bacterial infection, increased PCT level was significantly associated with lower gestational age and respiratory difficulty during the first week of life. Further studies are needed for clinical applications.

Early Treatment With Enalapril and Later Renal Injury in Programmed Obese Adult Rats.

Obesity-related kidney disease should be prevented or retarded. We aimed to investigate whether early treatment with enalapril ameliorates later renal injury induced by early postnatal overnutrition. Three or ten male pups per mother were assigned to either the Obese or Lean group during the first 21 days of life. These pups were treated with enalapril (Obese enalapril, OE; Lean enalapril, LE) or vehicle (Obese control, OC; Lean control, LC) for 15-28 days. Body weight, blood pressure (BP), and renal alterations were determined at 3 months. Enalapril decreased body weight only in the Lean group at 3 months (P < 0.05). Systemic BP levels were higher in the LE, OC, and OE groups than in the LC group at 3 months (P < 0.05). Fewer glomeruli per section area were found in the LE, OC, and OE groups than in the LC group and in the OE group than in the OC group (P < 0.05). The LE and OE groups had higher index scores of glomerulosclerosis and tubulointerstitial fibrosis than the controls (P < 0.05). LE pups showed increased intrarenal angiotensin II receptor type (AT)2 and matrix metalloproteinase (MMP)-9 and decreased renin and tissue inhibitor of MMP (TIMP)-1 expression than the LC rats (P < 0.05). OE pups showed increased intrarenal AT2 and decreased AT1 and TIMP-1 expression than the OC rats (P < 0.05). In conclusion, early treatment with enalapril can induce detrimental renal effects in later life and may not be renoprotective in programmed obese adult rats. J. Cell. Physiol. 232: 447-455, 2017. © 2016 Wiley Periodicals, Inc.

Impaired angiogenesis in the enalapril-treated neonatal rat kidney.

PURPOSE: Nephrogenesis is normally accompanied by a tightly regulated and efficient vascularization. We investigated the effect of angiotensin II inhibition on angiogenesis in the developing rat kidney. METHODS: Newborn rat pups were treated with enalapril (30 mg/kg/day) or vehicle (control) for 7 days after birth. Renal histological changes were checked using Hematoxylin & Eosin staining. We also investigated the intrarenal expression of vascular endothelial growth factor (VEGF)-A, VEGF receptor 1 (VEGFR1), VEGFR2, platelet-derived growth factor (PDGF)-B, and PDGF receptor-ß with Western blotting and immunohistochemical staining at postnatal day 8. Expression of the endothelial cell marker CD31 was examined to determine glomerular and peritubular capillary density. RESULTS: Enalapril-treated rat kidneys showed disrupted tubules and vessels when compared with the control rat kidneys. In the enalapril-treated group, intrarenal VEGF-A protein expression was significantly higher, whereas VEGFR1 protein expression was lower than that in the control group (P<0.05). The expression of VEGFR2, PDGF-B, and PDGF receptor-ß was not different between the 2 groups. The increased capillary CD31 expression on the western blots of enalapril-treated rat kidneys indicated that the total endothelial cell protein level was increased, while the cortical capillary density, assessed using CD31 immunohistochemical staining, was decreased. CONCLUSION: Impaired VEGF-VEGFR signaling and altered capillary repair may play a role in the deterioration of the kidney vasculature after blocking of angiotensin II during renal development.

Differential modification of enalapril in the kidneys of lean and 'programmed' obese male young rats.

OBJECTIVE: We investigated whether enalapril treatment could have beneficial effects on nutritionally-programmed renal changes in postnatally overfed young rats. METHODS: Three or 10 male pups per mother were assigned to either the Obese or Lean groups during the first 21 days of life. These pups were treated with enalapril (Obese enalapril, OE; Lean enalapril, LE) or vehicle (Obese control, OC; Lean control, LC) between 15 and 28 days. All pups had their kidneys examined at 29 days. RESULTS: OC pups weighed more than those in the LC group between 7 and 28 days of age (P<0.05). Enalapril reduced body weights in rats from both the Obese and Lean groups between 22 and 28 days (P<0.05). Renal cell proliferation and apoptosis, glomerulosclerosis, and tubulointerstitial fibrosis were all increased by enalapril (P<0.05). Among the groups, renal cell apoptosis and serum creatinine were the highest in OE pups (P<0.05). Enalapril treatment resulted in contrasting molecular expression profiles involved in renal maturation and repair in the kidneys of the rats from the Lean and Obese groups. CONCLUSION: Enalapril can differentially modulate renal molecular alterations in lean and postnatally overfed rats and may be not beneficial in obese young male rats.

Postnatal early overnutrition causes long-term renal decline in aging male rats.

BACKGROUND: We evaluated the influence of postnatal early overnutrition on renal pathophysiological changes in aging rats. METHODS: 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. RESULTS: 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). CONCLUSION: Early postnatal overnutrition can potentiate structural and functional abnormalities in the aging kidney and can lead to systolic hypertension with reduced intrarenal renin activity.

Application of array-based comparative genomic hybridization to pediatric neurologic diseases.

PURPOSE: Array comparative genomic hybridization (array-CGH) is a technique used to analyze quantitative increase or decrease of chromosomes by competitive DNA hybridization of patients and controls. This study aimed to evaluate the benefits and yield of array-CGH in comparison with conventional karyotyping in pediatric neurology patients. MATERIALS AND METHODS: We included 87 patients from the pediatric neurology clinic with at least one of the following features: developmental delay, mental retardation, dysmorphic face, or epilepsy. DNA extracted from patients and controls was hybridized on the Roche NimbleGen 135K oligonucleotide array and compared with G-band karyotyping. The results were analyzed with findings reported in recent publications and internet databases. RESULTS: Chromosome imbalances, including 9 cases detected also by G-band karyotyping, were found in 28 patients (32.2%), and at least 19 of them seemed to be causally related to the abnormal phenotypes. Regarding each clinical symptom, 26.2% of 42 developmental delay patients, 44.4% of 18 mental retardation patients, 42.9% of 28 dysmorphic face patients, and 34.6% of 26 epilepsy patients showed abnormal array results. CONCLUSION: Although there were relatively small number of tests in patients with pediatric neurologic disease, this study demonstrated that array-CGH is a very useful tool for clinical diagnosis of unknown genome abnormalities performed in pediatric neurology clinics.

Overweight, hypertension and renal dysfunction in adulthood of neonatally overfed rats.

Accelerated growth in early infancy has been associated with later cardiovascular and metabolic diseases. We investigated the influence of overnutrition during neonatal periods on the development of renal pathophysiological changes in adult offspring rats. Three or 10 male pups per mother were assigned to either the small litter (SL) or normal litter (NL) control groups during the first 21 days of life. The effects of early postnatal overnutrition on body weight, blood pressure and renal changes were determined at 3 and 6 months. Pups in the SL group weighed more than controls between 7 days and 6 months of age (P<.05). In the SL group, serum creatinine levels were higher at 3 and 6 months (P<.05), and at 6 months, blood pressure levels were higher than those of the controls (P<.05). The number of ED-1 positive macrophages in renal cortex and glomerulosclerosis index increased in the SL group at 3 and 6 months (P<.05). Additionally, cortical apoptotic cells increased in the SL group at 6 months (P<.05). Immunoblotting and immunohistochemistry showed that matrix metalloproteinase (MMP)-9 protein expressions decreased and tissue inhibitor of MMP-1, tumor necrosis factor-α, osteopontin and adiponectin expressions increased in the SL group at 3 months (P<.05). However, at 6 months, MMP-9 expression was elevated, and osteopontin expression remained elevated in the SL group (P<.05). Early postnatal overfeeding can lead to lasting overweight, hypertension and renal dysfunction and place a greater burden on the kidney.

Postnatal early overnutrition dysregulates the intrarenal renin-angiotensin system and extracellular matrix-linked molecules in juvenile male rats.

Overnutrition during the perinatal period has been associated with susceptibility to obesity and related comorbidities. We examined the effects of postnatal early overnutrition on the development of juvenile obesity and the associated renal pathophysiological changes. Three or 10 pups per mother from rat pup litters were assigned to either the overnutrition or control groups during the first 21 days of life. The effects of overfeeding were measured at 28 days. The smaller male litter pups were heavier than the controls between 4 and 28 days after birth (P<.05). By 28 days of age, the kidney weight per body weight ratio decreased in the small litter group (P<.05). Circulating leptin levels increased in the small litter rats (P<.05). Overnutrition had no effect on renal cell proliferation, apoptosis, macrophages and glomerulosclerosis. In the immunoblots and immunohistochemistry, renin and angiotensin II type (AT) 2 receptor expression increased in the overfed rats (P<.05). By contrast, the plasminogen activator inhibitor (PAI)-1 and matrix metalloproteinase (MMP)-9 expression decreased in the overnutrition group (P<.05). The AT 1 receptor, tissue inhibitor of MMP-1, monocyte chemoattractant protein-1, tumor necrosis factor-α, osteopontin and adiponectin expression was not changed. Our data showed that postnatal early overfeeding led to hyperleptinemia, juvenile obesity and the acquired reset of renal maturation. Up-regulation of renin and AT2 and down-regulation of PAI-1 and MMP-9 might contribute to abnormal programming of renal growth in rats exposed to postnatal early overnutrition.

Cellular and RAS changes in the hearts of young obese rats.

Obesity during childhood increases the risk of cardiac disease, hypertension, and other complications in adulthood. We investigated the cellular and renin-angiotensin system changes of the heart in obese young rats. We used Sprague-Dawley rats and early obesity was induced by overfeeding through adjusting the number of male pups per dam during the first 28 days of life. The body weight, heart weight, blood pressure, serum glucose, and blood pressure were assessed and we performed echocardiography, proliferating cell nuclear antigen (PCNA); assessment, apoptosis and Masson's trichrome staining, and Western blotting and the results were compared between the normal litter (NL, control) and the small litter (SL, obesity). There were no differences in blood pressure and serum glucose, but the body weight increased 61.2% and the interventricular septal thickness in diastole on the echocardiography was increased in the SL. There was hyperplasia of the PCNA cells and apoptotic cells without cellular hypertrophy or change of the amount of collagen in the SL. On Western blotting, rennin, and angiotensin II type 2 receptor (AT2R) were increased without a change of angiotensin II type 1 receptor (AT1R) in the SL. Early obesity caused echocardiographically detected septal hypertrophy and an increase of cellular turnover. Renin and AT2R were upregulated without a change of AT1R and the increase of AT2R was regarded as a cardioprotective effect against the pathologic conditions caused by the early obesity.

Spironolactone and enalapril differentially up-regulate the expression of VEGF and heme oxygenase-1 in the neonatal rat kidney.

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.

Hepatic and pulmonary nodular lesions in pediatric urinary tract infections.

One of the major goals in investigating children with urinary tract infection (UTI) is to recognize patients at risk of further UTI-related problems. This study reports the clinical features of 19 pediatric patients with UTIs in whom associated hepatic and/or pulmonary nodules were incidentally diagnosed by the imaging tests performed for the UTI. Hepatic nodules in five patients were detected on ultrasound scans, and pulmonary nodules and both hepatic and pulmonary nodules were detected in 12 and two children by dimercaptosuccinic acid scintigraphy. The mean age of the patients was 24.5 months. Vesicoureteral reflux (VUR) was detected in nine of 17 patients (52.9%), acute pyelonephritis was identified in nine of 18 patients, and renal scarring was found in 57.1% patients with pyelonephritis. On follow-up, the hepatic and/or pulmonary nodules regressed in all patients. About 85.7% of patients experienced a recurrence of UTI within 1 year. In comparison with age- and sex-matched controls with UTIs without pulmonary or hepatic nodules, the presence of VUR and the recurrence of UTI within 1 year were higher in patients with UTIs and nodules (P<0.05). The hepatic and/or pulmonary nodules identified on the ultrasound scan and by dimercaptosuccinic acid scintigraphy may provide a valuable diagnostic marker for the proper management of patients with an UTI.

Questionnaire survey on pediatric hypertension in Japan and Korea.

BACKGROUND: Hypertension (HTN) is no longer viewed as an adult disease. The purpose of the present study was to understand how hypertensive children are evaluated and managed, by surveying pediatricians in Japan and South Korea. METHODS: A questionnaire was mailed to 109 Japanese (JA) and 159 Korean (KO) pediatric cardiologists, pediatric nephrologists, and other pediatricians. RESULTS: A total of 127 replies were received (response rate 47%). Most of respondents did not check blood pressure (BP) routinely in outpatient clinics (JA 77%, KO 88%). A mercury sphygmomanometer was the most commonly used method for BP measurements (JA 72%, KO 62%). BP treatment goals were usually set at the 95th percentile for age, gender, and height (JA 47%, KO 54%). More KO used a lower goal in children with primary HTN than JA. KO respondents preferred angiotensin-converting enzyme inhibitors (ACEI) as initial agents regardless of underlying diseases whereas JA respondents chose various medications, that is, calcium channel blockers, diuretics, and ACEI. For BP monitoring, self-monitoring was found to be most frequent in both countries (JA 80%, KO 57%). Ambulatory BP monitoring was not frequently utilized in both countries (JA 33% KO 34%). CONCLUSION: The current assessment, management and differing trends in pediatric HTN in Japan and Korea have been identified in the present study. Pediatricians should be aware of the growing implications of HTN in children.

Endothelin A receptor blockade influences apoptosis and cellular proliferation in the developing rat kidney.

Endothelin systems are believed to play important roles in the emergence and maintenance of functions of various organs during perinatal development, including the kidney. The present study was designed to investigate the roles of endothelin systems on physiologic renal growth and development. Newborn rat pups were treated with either Bristol-Myers Squibb-182874 (30 mg/kg/day), a selective endothelin A receptor (ET(A)R) antagonist, or vehicle for 7 days. To identify cellular changes, kidneys were examined for apoptotic cells by terminal deoxynucleotide transferase-mediated nick-end labeling stain and proliferating cell nuclear antigen (PCNA) by immunohistochemical (IHC) stain. To clarify the molecular control of these processes, immunoblots and reverse transcriptase-polymerase chain reaction for Clusterin, Bcl-2, Bcl-X(L), Bax, and p53 were performed. ETAR antagonist treatment resulted in reduced kidney weights, decreased PCNA-positive proliferating cells, and increased apoptotic cells. The protein expressions of renal Bcl-X(L) and Bax in the ETAR antagonist-treated group were significantly decreased, whereas the mRNA expressions of these genes were not changed. There were no significant differences in the expressions of Clusterin, Bcl-2, and p53. In conclusion, inhibition of endogenous endothelins impairs renal growth, in which decreased cellular proliferation, increased apoptosis and decreased expressions of renal Bcl-X(L) and Bax are possibly implicated.