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The intrarenal renin–angiotensin system (RAS) has many well-documented pathophysiologic functions in both blood pressure regulation and renal disease development. Angiotensin II (Ang II) is the major bioactive product of the RAS. It induces inflammation, renal cell growth, mitogenesis, apoptosis, migration, and differentiation. In addition, Ang II regulates the gene expression of bioactive substances and activates multiple intracellular signaling pathways that are involved in renal damage. Activation of the Ang II type 1 (AT1) receptor pathway results in the production of proinflammatory mediators, intracellular formation of reactive oxygen species, cell proliferation, and extracellular matrix synthesis, which in turn facilities renal injury. Involvement of angiotensinogen (AGT) in intrarenal RAS activation and development of renal disease has previously been reported. Moreover, studies have demonstrated that the urinary excretion rates of AGT provide a specific index of the intrarenal RAS status. Enhanced intrarenal AGT levels have been observed in experimental models of renal disease, supporting the concept that AGT plays an important role in the development and progression of renal disease. In this review, we focus on the role of intrarenal RAS activation in the pathophysiology of renal disease. Additionally, we explored the potential of urinary AGT as a novel biomarker of intrarenal RAS status in renal disease.

Recently, there has been a paradigm shift away from an emphasis on the role of the endocrine (circulating) renin−angiotensin system (RAS) in the regulation of the sodium and extracellular fluid balance, blood pressure, and the pathophysiology of hypertensive organ damage toward a focus on the role of tissue RAS found in many organs, including kidney. A tissue RAS implies that RAS components necessary for the production of angiotensin II (Ang II) reside within the tissue and its production is regulated within the tissue, independent of the circulating RAS. Locally produced Ang II plays a role in many physiological and pathophysiological processes such as hypertension, inflammation, oxidative stress, and tissue fibrosis. Both glomerular and tubular compartments of the kidney have the characteristics of a tissue RAS. The purpose of this article is to review the recent advances in tissue RAS research with a particular focus on the role of the glomerular RAS in the progression of renal disease.

PurposeProton magnetic resonance spectroscopy (1H MRS) is a noninvasive neuroimaging method to quantify biochemical metabolites in vivo and it can serve as a powerful tool to monitor neurobiochemical profiles in the brain. Asperger's syndrome (AS) is a type of autism spectrum disorder, which is characterized by impaired social skills and restrictive, repetitive patterns of interest and activities, while intellectual levels and language skills are relatively preserved. Despite clinical aspects have been well-characterized, neurometabolic profiling in the brain of AS remains to be clear. The present study used proton magnetic resonance spectroscopy (1H MRS) to investigate whether pediatric AS is associated with measurable neurometabolic abnormalities that can contribute new information on the neurobiological underpinnings of the disorder.MethodsStudy participants consisted of 34 children with AS (2-12 years old; mean age 5.2 (±2.0); 28 boys) and 19 typically developed children (2-11 years old; mean age 5.6 (±2.6); 12 boys) who served as the normal control group. The 1H MRS data were obtained from two regions of interest: the anterior cingulate cortex (ACC) and left cerebellum.ResultsIn the ACC, levels of N-acetylaspartate (NAA), total creatine (tCr), total choline-containing compounds (tCho) and myo-Inositol (mI) were significantly decreased in children with AS compared to controls. On the other hand, no significant group differences in any of the metabolites were found in the left cerebellum. Neither age nor sex accounted for the metabolic findings in the regions.ConclusionThe finding of decreased levels of NAA, tCr, tCho, and mI in the ACC but not in left cerebellar voxels in the AS, suggests a lower ACC neuronal density in the present AS cohort compared to controls.

BackgroundThere have been only a few large-scale cohort studies that have reviewed accumulated cases of thrombotic microangiopathy (TMA). The aim of this study was to collect and analyze TMA cases based on the renal biopsy, as a nationwide survey in Japan.MethodsIn this cross-sectional study, large nationwide data from the Japan Renal Biopsy Registry (J-RBR) were used. Among the patients registered in the J-RBR online system from July 2007 to July 2017, TMA cases were extracted and epidemiological data and clinical findings were investigated.ResultsOut of the 38,495 patients enrolled in a period of 10 years, 152 (0.39%) cases had been diagnosed with TMA. The patient age was widely distributed, including 9.2%, 66.4%, and 24.3% for children, adults, and the elderly, respectively. There were various causes of TMA. Among them, hemolytic uremic syndrome (HUS)/thrombotic thrombocytopenic purpura (TTP) (16.4%), connective tissue disease (CTD)-related (17.1%), and drug-induced (16.4%) were frequently observed. The background factors of TMA were different in children and adults. In a comparison between groups consisting of HUS/TTP, CTD-related, and drug-induced, the HUS/TTP group was significantly younger (p = 0.01), and the drug-induced TMA group tended to have a high urinary protein positive rate (p = 0.05). A comparative analysis according to the age group showed significantly higher serum creatinine levels in the elderly (p < 0.01).ConclusionThis is the first report of epidemiological and clinical data of biopsy-proven TMA in Japan. The characteristics of TMA with diversity based on the underlying disease and age group were reported.

A disintegrin and metalloprotease 17 (ADAM17) is the major sheddase that processes more than 80 substrates, including tumour necrosis factor-α (TNFα). The homozygous genetic deficiency of ADAM17 causing a complete loss of ADAM17 expression was reported to be linked to neonatal inflammatory skin and bowel disease 1 (NISBD1). Here we report for the first time, a family with NISBD1 caused by functionally confirmed compound heterozygous missense variants of ADAM17 , namely c.1699T>C (p.Cys567Arg) and c.1799G>A (p.Cys600Tyr). Both variants were detected in two siblings with clinical features of NISBD1, such as erythroderma with exudate in whole body, recurrent skin infection and sepsis and prolonged diarrhoea . In a cell-based assay using Adam10/17 double-knockout mouse embryonic fibroblasts ( Adam10 / 17 −/− mEFs) exogenously expressing each of these mutants, phorbol 12-myristate 13-acetate-stimulated shedding was strongly reduced compared with wild-type ADAM17. Thus, in vitro functional assays demonstrated that both missense variants cause the loss-of-function of ADAM17, resulting in the development of NISBD1. Our study further expands the spectrum of genetic pathology underlying ADAM17 in NISBD1 and establishes functional assay systems for its missense variants.

BackgroundThe current study tested the hypothesis that urinary angiotensinogen (UAGT) and urinary monocyte chemoattractant protein-1 (UMCP-1) levels provide a specific index of intrarenal renin–angiotensin system (RAS) status and the degree of infiltration of macrophages associated with RAS blockade and immunosuppressant treatment in pediatric patients with chronic glomerulonephritis.MethodsWe measured baseline UAGT and UMCP-1 levels to examine the correlation between glomerular injury in 48 pediatric chronic glomerulonephritis patients before treatment. Furthermore, we performed immunohistochemical analysis of angiotensinogen (AGT) and CD68 in 27 pediatric chronic glomerulonephritis patients treated with RAS blockades and immunosuppressants for 2 years. Finally, we examined the effects of angiotensin II (Ang II) on monocyte chemoattractant protein-1 (MCP-1) expression in cultured human mesangial cells (MCs).ResultsBaseline UAGT and UMCP-1 levels positively correlated with urinary protein levels, scores for mesangial hypercellularity, rate of crescentic formation, and expression levels of AGT and CD68 in renal tissues (p < 0.05). UAGT and UMCP-1 levels were significantly decreased after RAS blockade and immunosuppressant treatment (p < 0.01), which was accompanied by AGT and CD68 (p < 0.01), as well as the magnitude of glomerular injury. Cultured human MCs showed increased MCP-1 messenger ribonucleic acid and protein levels after Ang II treatment (p < 0.01).ConclusionsThe data indicates that UAGT and UMCP-1 are useful biomarkers of the degree of glomerular injury during RAS blockade and immunosuppressant treatment in pediatric patients with chronic glomerulonephritis.

BackgroundChildren with low birth weight (LBW) have an increased risk of developing chronic kidney disease (CKD), and no effective strategies have been established to prevent the progression of CKD in these patients. Urinary angiotensinogen (UAGT) may represent a useful marker of intrarenal renin–angiotensin system (RAS) activation, which has been suggested to play a critical role in the development of hypertension and CKD. Herein, we conducted a prospective study to determine whether RAS blockade is beneficial for suppressing the progression of CKD in children with LBW, using UAGT as a surrogate marker of renal impairment.MethodsNine children with CKD (stages: 1–2) who had very low birth weight (VLBW; < 1500 g) were started on RAS blockade with candesartan. We measured blood pressure and laboratory parameters, including urinary concentrations of angiotensinogen, protein, albumin, creatinine (Cr), and estimated glomerular filtration rate (eGFR), before and after candesartan treatment.ResultsBirth weight was 712 g (range, 536–800 g). Age at evaluation was 11.6 years (range, 10.3–15.6 years). After candesartan treatment for 47.6 ± 25.0 months, the UAGT to urinary Cr ratio decreased from 61.9 ± 44.7 to 16.8 ± 14.4 μg/g (p = 0.015). The urinary protein to Cr and albumin to Cr ratios also decreased (p = 0.008 and p = 0.012, respectively), whereas there was no significant change in eGFR.ConclusionsRAS blockade reduced UAGT levels and improved proteinuria/albuminuria in children with CKD who had VLBW. Suppression of intrarenal RAS activity may slow the progression of CKD in children with LBW.

Although a recent study demonstrated that the (pro)renin receptor ((P)RR) was highly expressed in the developing kidney during the mouse embryonic development, the mechanism by which (P)RR supports renal development in humans is not fully understood. In this study, we examined the plasma levels of (pro)renin and soluble (P)RR (s(P)RR) in cord blood and neonates as well as (P)RR expression in human kidney tissues. Samples were collected from 57 preterm and 67 full-term human neonates. (Pro)renin and s(P)RR levels were measured using enzyme-linked immunosorbent assays. Additionally, we performed an immunohistochemical (IHC) analysis of kidney tissues from neonates and minor glomerular abnormalities in order to assess (P)RR expression in the kidney. Plasma (pro)renin and s(P)RR levels in cord blood were significantly higher in preterm neonates than in full-term neonates. Four weeks after birth, these differences were no longer evident for either plasma (pro)renin or s(P)RR levels between the two groups. Importantly, plasma (pro)renin and s(P)RR levels in cord blood were inversely correlated with gestational age. Furthermore, IHC indicated that renal expression levels of (P)RR in neonates were stronger than those in minor glomerular abnormalities. Conclusion : (P)RR may play a pivotal role in prenatal renal development in humans. What is Known: • Renal renin-angiotensin system (RAS) has several pathophysiologic functions not only in blood pressure regulation but also in pediatric renal disease. • Renal RAS activation plays a key role of renal development during gestation. What is New : • Plasma (pro)renin and soluble (pro)renin receptor (s(P)RR) levels in cord blood were significantly higher in preterm neonates than in full-term neonates. • Immunohistochemical analysis of kidney tissue indicated that renal expression levels of (P)RR in neonates were stronger than in minor glomerular abnormalities.

The Japan Renal Biopsy Registry (J-RBR) was started in 2007 and the Japan Kidney Disease Registry (J-KDR) was then started in 2009 by the Committee for Standardization of Renal Pathological Diagnosis and the Committee for the Kidney Disease Registry of the Japanese Society of Nephrology. The purpose of this report is to describe and summarize the registered data from 2009 and 2010. For the J-KDR, data were collected from 4,016 cases, including 3,336 (83.1 %) by the J-RBR and 680 (16.9 %) other cases from 59 centers in 2009, and from 4,681 cases including 4,106 J-RBR cases (87.7 %) and 575 other cases (12.3 %) from 94 centers in 2010, including the affiliate hospitals. In the J-RBR, 3,165 native kidneys (94.9 %) and 171 renal grafts (5.1 %) and 3,869 native kidneys (94.2 %) and 237 renal grafts (5.8 %) were registered in 2009 and 2010, respectively. Patients younger than 20 years of age comprised 12.1 % of the registered cases, and those 65 years and over comprised 24.5 % of the cases with native kidneys in 2009 and 2010. The most common clinical diagnosis was chronic nephritic syndrome (55.4 % and 50.0 % in 2009 and 2010, respectively), followed by nephrotic syndrome (22.4 % and 27.0 %); the most frequent pathological diagnosis as classified by the pathogenesis was IgA nephropathy (31.6 % and 30.4 %), followed by primary glomerular diseases (except IgA nephropathy) (27.2 % and 28.1 %). Among the primary glomerular diseases (except IgA nephropathy) in the patients with nephrotic syndrome, membranous nephropathy was the most common histopathology in 2009 (40.3 %) and minor glomerular abnormalities (50.0 %) were the most common in 2010 in native kidneys in the J-RBR. Five new secondary and longitudinal research studies by the J-KDR were started in 2009 and one was started in 2010.

Hypoxia and low pulmonary arterial (PA) blood flow stimulate the development of systemic-to-pulmonary collateral blood vessels, which can be an adverse factor when performing the Fontan operation. The aim of this study was to use optical coherence tomography (OCT) to elucidate the morphological changes in PA vasculature after creation of a bidirectional cavopulmonary connection (BCPC) in children. This prospective study evaluated PA wall thickness and development of PA vasa vasorum (VV) in the distal PA of eight patients (BCPC group, 1.3 ± 0.3 years) and 20 age-matched children with normal pulmonary artery hemodynamics and morphology (Control group, 1.4 ± 0.3 years). VV development was defined by the VV area ratio, defined as the VV area divided by the adventitial area in cross-sectional images. There was no significant difference in PA wall thickness between the BCPC and control groups (0.12 ± 0.03 mm vs. 0.12 ± 0.02 mm, respectively). The VV area ratio was significantly greater in the BCPC group than in the Control group (14.5 ± 3.5% vs. 5.3 ± 1.6%, respectively; p<0.0001). OCT is a promising new tool for evaluating PA pathology, including the development of VV in patients after BCPC.