Key Points Transcription factor 21 in Foxd1+ interstitial progenitors is required for proliferation and differentiation of the renal stroma. Tcf21 binds to β -catenin and enhances expression of stromal Wnt target genes. The kidney stroma is critical for normal development of the nephron progenitor cells, loop of Henle, and collecting ducts. Background Kidney formation requires coordinated interactions between multiple cell types. Input from the interstitial progenitor cells is implicated in multiple aspects of kidney development. We previously reported that transcription factor 21 (Tcf21) is required for ureteric bud branching. Here, we show that Tcf21 in Foxd1+ interstitial progenitors regulates stromal formation and differentiation via interaction with β -catenin. Methods We utilized the Foxd1Cre;Tcf21 f/f murine kidney for morphologic analysis. We used the murine clonal mesenchymal cell lines MK3/M15 to study Tcf21 interaction with Wnt/ β -catenin. Results Absence of Tcf21 from Foxd1+ stromal progenitors caused a decrease in stromal cell proliferation, leading to marked reduction of the medullary stromal space. Lack of Tcf21 in the Foxd1+ stromal cells also led to defective differentiation of interstitial cells to smooth-muscle cells, perivascular pericytes, and mesangial cells. Foxd1Cre;Tcf21 f/f kidney showed an abnormal pattern of the renal vascular tree. The stroma of Foxd1Cre;Tcf21 f/f kidney demonstrated marked reduction in β -catenin protein expression compared with wild type. Tcf21 was bound to β -catenin both upon β -catenin stabilization and at basal state as demonstrated by immunoprecipitation in vitro . In MK3/M15 metanephric mesenchymal cells, Tcf21 enhanced TCF/LEF promoter activity upon β -catenin stabilization, whereas DNA-binding deficient mutated Tcf21 did not enhance TCF/LEF promoter activity. Kidney explants of Foxd1Cre;Tcf21 f/f showed low mRNA expression of stromal Wnt target genes. Treatment of the explants with CHIR, a Wnt ligand mimetic, restored Wnt target gene expression. Here, we also corroborated previous evidence that normal development of the kidney stroma is required for normal development of the Six2+ nephron progenitor cells, loop of Henle, and the collecting ducts. Conclusions These findings suggest that stromal Tcf21 facilitates medullary stroma development by enhancing Wnt/ β -catenin signaling and promotes stromal cell proliferation and differentiation. Stromal Tcf21 is also required for the development of the adjacent nephron epithelia.
Prematurity is a risk factor for elevated blood pressure (BP). We performed a mixed-methods study of care patterns and awareness of early BP screening recommendations for infants born prematurely (IBP) by interviewing/surveying providers on practice- and provider-level BP screening. IBP's records were reviewed for BP screening documentation, demographics, and gestational age (GA). Visits <33 months were reviewed for anthropometrics, BP, and comorbidities. Chi-square analysis evaluated BP screening by GA and comorbidities. Twenty-six of 49 practices completed interviews; 81% had infant BP equipment available; 4% had BP measurement protocol for IBP. Twenty-eight of 86 providers were aware of screening guidelines; none reported routine assessment. Twenty-eight of 118 IBP had ≥1 BP documented; 43% had BP ≥90th percentile. Screening did not differ by GA group. Kidney-related diagnosis was associated with more frequent BP screening (P = .0454). BP is not routinely measured though often elevated before age 3 in IBP.
Aspergillus flavus causes invasive external otitis associated with severe infection of the skull base. A combination of amphotericin B, surgical debridement and long-term itraconazole is considered the therapy of choice. We report a case of invasive external otitis due to A. flavus that was treated successfully with a short course of amphotericin B and long-term oral itraconazole without surgical intervention.
Focusing on critically ill children with cardiac disease, we will review common causes of fluid perturbations, clinical recognition, and strategies to minimize and treat fluid-related complications.MEDLINE and PubMed.Meticulous fluid management is vital in critically ill children with cardiac disease. Fluid therapy is important to maintain adequate blood volume and perfusion pressure in order to support cardiac output, tissue perfusion, and oxygen delivery. However, fluid overload and acute kidney injury are common and are associated with increased morbidity and mortality. Understanding the etiologies for disturbances in volume status and the pathophysiology surrounding those conditions is crucial for providing optimal care.
Renin is crucial for blood pressure regulation and electrolyte balance, and its expressing cells arise from Foxd1+ stromal progenitors. However, factors guiding these progenitors toward renin-secreting cell fate remain unclear. Tcf21, a basic helix-loop-helix (bHLH) transcription factor, is essential in kidney development. Utilizing
Autosomal recessive polycystic kidney disease (ARPKD) is a severe renal disease. Kidneys and liver may be affected clinically but at a varying severity, ranging from a Potter-like syndrome, systemic hypertension and variable renal dysfunction to portal hypertension due to hepatic fibrosis. Most ARPKD cases are caused by mutations in the gene PKHD1. Specific mutations in patients from various ethnic backgrounds have been described, most cases being compound heterozygotes. The genotype-phenotype correlation has not been sufficiently studied.a) Clinical characterization of ARPKD patients in Southern Israel. b) Establishment of a genetic method for prenatal diagnosis of the disease.Clinical data of all ARPKD cases diagnosed in our institution was retrospectively analyzed. DNA samples were collected from the patients, parents and siblings. Linkage analysis was used to verify individual genetic status.Eighteen ARPKD patients from 7 extended Bedouin families were identified (perinatal manifestation = 9; neonatal = 2; infantile = 2; juvenile = 5). The family trees in all cases were highly suggestive of a founder effect, implying that affected individuals were very likely to harbor identical mutations on both ARPKD alleles. Inter- and intra-familial phenotypic variability was found in several families. Linkage analysis using polymorphic markers specific to the chromosome 6p-PKHD1 locus was established in our laboratory and was found to be reliable, thereby assisting in prenatal diagnosis in known ARPKD families.Phenotypic variability exists in ARPKD, even among families with supposedly homozygous mutations in the PKHD1 gene. We have established a reliable method for prenatal diagnosis of the disease by linkage analysis, thus enabling future diagnosis in families at risk.
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