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Bradley K Yoder - One of the best experts on this subject based on the ideXlab platform.
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resident macrophages in Cystic Kidney Disease
Kidney, 2021Co-Authors: Kurt A Zimmerman, Bradley K YoderAbstract:Interstitial inflammation is an important feature of Cystic Kidney Disease. Renal macrophages are the most well-studied inflammatory cell in the Kidney, and their involvement in cyst formation has been reported in different animal models and patients with Cystic Kidney Disease. Originally, it was believed that renal macrophages were maintained from a constant supply of bone marrow–derived circulating monocytes, and could be recruited to the Kidney in response to local inflammation. However, this idea has been challenged using fate-mapping methods, by showing that at least two distinct developmental origins of macrophages are present in the adult mouse Kidney. The first type, infiltrating macrophages, are recruited from circulating monocytes and gradually develop macrophage properties on entering the Kidney. The second, resident macrophages, predominantly originate from embryonic precursors, colonize the Kidney during its development, and proliferate in situ to maintain their population throughout adulthood. Infiltrating and resident macrophages work together to maintain homeostasis and properly respond to pathologic conditions, such as AKI, Cystic Kidney Disease, or infection. This review will briefly summarize current knowledge of resident macrophages in Cystic Kidney Disease.
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ectopic phosphorylated creb marks dedifferentiated proximal tubules in Cystic Kidney Disease
American Journal of Pathology, 2018Co-Authors: Pawan Puri, Caitlin Schaefer, Daniel Bushnell, Mary E Taglienti, Jordan A Kreidberg, Bradley K Yoder, Carlton M. BatesAbstract:Ectopic cAMP signaling is pathologic in polyCystic Kidney Disease; however, its spatiotemporal actions are unclear. We characterized the expression of phosphorylated Creb (p-Creb), a target and mediator of cAMP signaling, in developing and Cystic Kidney models. We also examined tubule-specific effects of cAMP analogs in cystogenesis in embryonic Kidney explants. In wild-type mice, p-Creb marked nephron progenitors (NP), early epithelial NP derivatives, ureteric bud, and cortical stroma; p-Creb was present in differentiated thick ascending limb of Henle, collecting duct, and stroma; however, it disappeared in mature NP-derived proximal tubules. In Six2cre;Frs2αFl/Fl mice, a renal Cystic model, ectopic p-Creb stained proximal tubule-derived Cystic segments that lost the differentiation marker lotus tetragonolobus lectin. Furthermore, lotus tetragonolobus lectin-negative/p-Creb-positive cyst segments (re)-expressed Ncam1, Pax2, and Sox9 markers of immature nephron structures and dedifferentiated proximal tubules after acute Kidney injury. These dedifferentiation markers were co-expressed with p-Creb in renal cysts in Itf88 knockout mice subjected to ischemia and Six2cre;Pkd1Fl/Fl mice, other renal cystogenesis models. 8-Br-cAMP addition to wild-type embryonic Kidney explants induced proximal tubular cystogenesis and p-Creb expression; these effects were blocked by co-addition of protein kinase A inhibitor. Thus p-Creb/cAMP signaling is appropriate in NP and early nephron derivatives, but disappears in mature proximal tubules. Moreover, ectopic p-Creb expression/cAMP signaling marks dedifferentiated proximal tubular Cystic segments. Furthermore, proximal tubules are predisposed to become Cystic after cAMP stimulation.
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microtubule modifications and stability are altered by cilia perturbation and in Cystic Kidney Disease
Cytoskeleton, 2013Co-Authors: Nicolas F Berbari, Lisa M Guaywoodford, Neeraj Sharma, Erik B Malarkey, Jay N Pieczynski, Ravindra Boddu, Jacek Gaertig, Bradley K YoderAbstract:Disruption of the primary cilium is associated with a growing number of human Diseases collectively termed ciliopathies. Ciliopathies present with a broad range of clinical features consistent with the near ubiquitous nature of the organelle and its role in diverse signaling pathways throughout development and adult homeostasis. The clinical features associated with cilia dysfunction can include such phenotypes as polyCystic Kidneys, skeletal abnormalities, blindness, anosmia, and obesity. Although the clinical relevance of the primary cilium is evident, the effects that cilia dysfunction has on the cell and how this contributes to Disease remains poorly understood. Here, we show that loss of ciliogenesis genes such as Ift88 and Kif3a lead to increases in post-translational modifications on cytosolic microtubules. This effect was observed in cilia mutant Kidney cells grown in vitro and in vivo in Cystic Kidneys. The hyper-acetylation of microtubules resulting from cilia loss is associated with both altered microtubule stability and increased α-tubulin acetyl-transferase activity. Intriguingly, the effect on microtubules was also evident in renal samples from patients with autosomal recessive polyCystic Kidneys. These findings indicate that altered microtubule post-translational modifications may influence some of the phenotypes observed in ciliopathies.
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normal ciliogenesis requires synergy between the Cystic Kidney Disease genes mks 3 and nphp 4
Journal of The American Society of Nephrology, 2010Co-Authors: Corey L Williams, Svetlana V Masyukova, Bradley K YoderAbstract:Cilia dysfunction contributes to renal cyst formation in multiple human syndromes including nephronophthisis (NPHP), Meckel-Gruber syndrome (MKS), Joubert syndrome (JBTS), and Bardet-Beidl syndrome (BBS). Although genetically heterogeneous, these Diseases share several loci that affect cilia and/or basal body proteins, but the functions and interactions of these gene products are incompletely understood. Here, we report that the ciliated sensory neurons (CSNs) of C. elegans express the putative transmembrane protein MKS-3, which localized to the distal end of their dendrites and to the cilium base but not to the cilium itself. Localization of MKS-3 and other known MKS and NPHP proteins partially overlapped. By analyzing mks-3 mutants, we found that ciliogenesis did not require MKS-3; instead, cilia elongated and cilia-mediated chemoreception was abnormal. Genetic analysis indicated that mks-3 functions in a pathway with other mks genes. Furthermore, mks-1 and mks-3 genetically interacted with a separate pathway (involving nphp-1 and nphp-4) to influence proper positioning, orientation, and formation of cilia. Combined disruption of nphp and mks pathways had cell nonautonomous effects on C. elegans sensilla. Taken together, these data demonstrate the importance of mutational load on the presentation and severity of ciliopathies and expand the understanding of the interactions between ciliopathy genes.
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disruption of intraflagellar transport in adult mice leads to obesity and slow onset Cystic Kidney Disease
Current Biology, 2007Co-Authors: James R Davenport, Amanda J Watts, Venus C Roper, Mandy J Croyle, Thomas Van Groen, Michael J Wyss, Tim R Nagy, Robert A Kesterson, Bradley K YoderAbstract:The assembly of primary cilia is dependent on intraflagellar transport (IFT), which mediates the bidirectional movement of proteins between the base and tip of the cilium. In mice, congenic mutations disrupting genes required for IFT (e.g., Tg737 or the IFT kinesin Kif3a) are embryonic lethal, whereas Kidney-specific disruption of IFT results in severe, rapidly progressing Cystic pathology. Although the function of primary cilia in most tissues is unknown, in the Kidney they are mechanosenstive organelles that detect fluid flow through the tubule lumen. The loss of this flow-induced signaling pathway is thought to be a major contributing factor to cyst formation. Recent data also suggest that there is a connection between ciliary dysfunction and obesity as evidenced by the discovery that proteins associated with human obesity syndromes such as Alstrom and Bardet-Biedl localize to this organelle. To more directly assess the importance of cilia in postnatal life, we utilized conditional alleles of two ciliogenic genes (Tg737 and Kif3a) to systemically induce cilia loss in adults. Surprisingly, the Cystic Kidney pathology in these mutants is dependent on the time at which cilia loss was induced, suggesting that cyst formation is not simply caused by impaired mechanosensation. In addition to the Cystic pathology, the conditional cilia mutant mice become obese, are hyperphagic, and have elevated levels of serum insulin, glucose, and leptin. We further defined where in the body cilia are required for normal energy homeostasis by disrupting cilia on neurons throughout the central nervous system and on pro-opiomelanocortin-expressing cells in the hypothalamus, both of which resulted in obesity. These data establish that neuronal cilia function in a pathway regulating satiety responses.
Anthony J Bleyer - One of the best experts on this subject based on the ideXlab platform.
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autosomal dominant tubulointerstitial Kidney Disease diagnosis classification and management a kdigo consensus report
Kidney International, 2015Co-Authors: Kaiuwe Eckardt, Anthony J Bleyer, Corinne Antignac, Karin Dahan, Constantinos Deltas, Seth L Alper, Dominique Chauveau, Andrew Hosking, Stanislav KmochAbstract:Rare autosomal dominant tubulointerstitial Kidney Disease is caused by mutations in the genes encoding uromodulin ( UMOD ), hepatocyte nuclear factor-1β ( HNF1B ), renin ( REN ), and mucin-1 ( MUC1 ). Multiple names have been proposed for these disorders, including ‘Medullary Cystic Kidney Disease (MCKD) type 2', ‘Familial Juvenile Hyperuricemic Nephropathy (FJHN)', or ‘Uromodulin-Associated Kidney Disease (UAKD)' for UMOD-related Diseases and ‘MCKD type 1' for the Disease caused by MUC1 mutations. The multiplicity of these terms, and the fact that cysts are not pathognomonic, creates confusion. Kidney Disease: Improving Global Outcomes (KDIGO) proposes adoption of a new terminology for this group of Diseases using the term ‘Autosomal Dominant Tubulointerstitial Kidney Disease' (ADTKD) appended by a gene-based subclassification, and suggests diagnostic criteria. Implementation of these recommendations is anticipated to facilitate recognition and characterization of these monogenic Diseases. A better understanding of these rare disorders may be relevant for the tubulointerstitial fibrosis component in many forms of chronic Kidney Disease.
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variable clinical presentation of an muc1 mutation causing medullary Cystic Kidney Disease type 1
Clinical Journal of The American Society of Nephrology, 2014Co-Authors: Anthony J Bleyer, John R Kelsoe, Corinne Antignac, Philip J Klemmer, Stanislav Kmoch, Vicki Robins, Kendrah Kidd, Gerald A Hladik, Stephen J Knohl, Steven J ScheinmanAbstract:Background and objectives The genetic cause of medullary Cystic Kidney Disease type 1 was recently identified as a cytosine insertion in the variable number of tandem repeat region of MUC1 encoding mucoprotein-1 (MUC1), a protein that is present in skin, breast, and lung tissue, the gastrointestinal tract, and the distal tubules of the Kidney. The purpose of this investigation was to analyze the clinical characteristics of families and individuals with this mutation. Design, setting, participants, & measurements Families with autosomal dominant interstitial Kidney Disease were referred for genetic analysis over a 14-year period. Families without UMOD or REN mutations prospectively underwent genotyping for the presence of the MUC1 mutation. Clinical characteristics were retrospectively evaluated in individuals with the MUC1 mutation and historically affected individuals (persons who were both related to genetically affected individuals in such a way that ensured that they could be genetically affected and had a history of CKD stage IV or Kidney failure resulting in death, dialysis, or transplantation). Results Twenty-four families were identified with the MUC1 mutation. Of 186 family members undergoing MUC1 mutational analysis, the mutation was identified in 95 individuals, 91 individuals did not have the mutation, and111 individuals were identified as historically affected. Individuals with the MUC1 mutation suffered from chronic Kidney failure with a widely variable age of onset of end stage Kidney Disease ranging from 16 to >80 years. Urinalyses revealed minimal protein and no blood. Ultrasounds of 35 individuals showed no medullary cysts. There were no clinical manifestations of the MUC1 mutation detected in the breasts, skin, respiratory system, or gastrointestinal tract. Conclusion MUC1 mutation results in progressive chronic Kidney failure with a bland urinary sediment. The age of onset of end stage Kidney Disease is highly variable, suggesting that gene–gene or gene–environment interactions contribute to phenotypic variability.
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clinico pathologic findings in medullary Cystic Kidney Disease type 2
Pediatric Nephrology, 2005Co-Authors: Anthony J Bleyer, Thomas C Hart, Mark C Willingham, Samy S Iskandar, Michael C Gorry, Howard TrachtmanAbstract:Medullary Cystic Kidney Disease type 2 is an uncommon autosomal dominant condition characterized by juvenile onset hyperuricemia, precocious gout and chronic renal failure progressing to end-stage renal Disease in the 4th through 7th decades of life. A family suffering from this condition is described. The patient in the index case presented with renal insufficiency as a child. A renal biopsy revealed tubular atrophy, and immunohistochemical staining of the tissue for uromodulin (Tamm Horsfall protein) revealed dense deposits in renal tubular cells. Genetic testing revealed a single nucleotide mutation (c.899G>A) resulting in an exchange of a cysteine residue for tyrosine (C300Y). Medullary Cystic Kidney Disease type 2 (also known as uromodulin-associated Kidney Disease) likely represents a form of endoplasmic reticulum storage Disease, with deposition of the abnormal uromodulin protein in the endoplasmic reticulum, leading to tubular cell atrophy and death.
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mutations of the umod gene are responsible for medullary Cystic Kidney Disease 2 and familial juvenile hyperuricaemic nephropathy
Journal of Medical Genetics, 2002Co-Authors: Thomas C Hart, Michael C Gorry, P S Hart, A S Woodard, Zak K Shihabi, Jaspreet S Sandhu, Brian H Shirts, H Zhu, Michael M Barmada, Anthony J BleyerAbstract:Introduction: Medullary Cystic Kidney Disease 2 (MCKD2) and familial juvenile hyperuricaemic nephropathy (FJHN) are both autosomal dominant renal Diseases characterised by juvenile onset of hyperuricaemia, gout, and progressive renal failure. Clinical features of both conditions vary in presence and severity. Often definitive diagnosis is possible only after significant pathology has occurred. Genetic linkage studies have localised genes for both conditions to overlapping regions of chromosome 16p11-p13. These clinical and genetic findings suggest that these conditions may be allelic. Aim: To identify the gene and associated mutation(s) responsible for FJHN and MCKD2. Methods: Two large, multigenerational families segregating FJHN were studied by genetic linkage and haplotype analyses to sublocalise the chromosome 16p FJHN gene locus. To permit refinement of the candidate interval and localisation of candidate genes, an integrated physical and genetic map of the candidate region was developed. DNA sequencing of candidate genes was performed to detect mutations in subjects affected with FJHN (three unrelated families) and MCKD2 (one family). Results: We identified four novel uromodulin ( UMOD) gene mutations that segregate with the Disease phenotype in three families with FJHN and in one family with MCKD2. Conclusion: These data provide the first direct evidence that MCKD2 and FJHN arise from mutation of the UMOD gene and are allelic disorders. UMOD is a GPI anchored glycoprotein and the most abundant protein in normal urine. We postulate that mutation of UMOD disrupts the tertiary structure of UMOD and is responsible for the clinical changes of interstitial renal Disease, polyuria, and hyperuricaemia found in MCKD2 and FJHN.
G H Mostbeck - One of the best experts on this subject based on the ideXlab platform.
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prevalence of acquired Cystic Kidney Disease and tumors in native Kidneys of renal transplant recipients a prospective us study
Radiology, 1995Co-Authors: Gertraud Heinzpeer, Maria Schoder, Thomas Rand, G Mayer, G H MostbeckAbstract:PURPOSE: To determine the prevalence of acquired Cystic Kidney Disease (ACKD) and renal neoplasms in the native Kidneys of renal transplant recipients. MATERIALS AND METHODS: The ultrasound (US) scans in 385 renal allograft recipients were prospectively studied. In addition, 65 patients with ACKD underwent two additional US examinations on different days to assess intra- and interobserver variability with regard to the number of cysts and their diameter. RESULTS: ACKD was present in 96 of 385 patients. Patients with ACKD were significantly older than patients without ACKD, had undergone hemodialysis for a longer period, and were predominantly men. There was no significant difference in the time with functioning graft. Renal cell carcinoma (RCC) was diagnosed in six patients at histologic examination. Of these six patients, five had evidence of ACKD. CONCLUSION: The frequency of ACKD increases with the duration of hemodialysis. The risk for the development of ACKD is increased in men and older patients. Th...
D Cameron - One of the best experts on this subject based on the ideXlab platform.
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autosomal dominant primary hyperparathyroidism and jaw tumor syndrome associated with renal hamartomas and Cystic Kidney Disease linkage to 1q21 q32 and loss of the wild type allele in renal hamartomas
The Journal of Clinical Endocrinology and Metabolism, 1996Co-Authors: Bin Tean Teh, Hunter Heath, Filip Farnebo, U Kristoffersson, B Sundelin, John Cardinal, R Axelson, Alpha S Yap, M Epstein, D CameronAbstract:Hereditary hyperparathyroidism-jaw tumor syndrome (HPT-JT) is an autosomal dominant Disease (OMIM 145001) that has recently been mapped to chromosomal region 1q21-q32 (HRPT2). Here we report two families with HPT-JT syndrome in which adult renal hamartomas or Cystic Kidney Disease were prominent associated features, possibly representing a new phenotypic variant of the HPT-JT syndrome. In the first family, renal lesions were present in five out of six affected individuals, whereas HPT and JT were seen in four and two cases, respectively. In the second family, JT was found in three of the five affected individuals and two affected members also exhibited polyCystic Kidney Disease. The possibility of the latter cosegregating as a separate autosomal dominant gene can not be ruled out. A sex-dependent penetrance of primary HPT, resulting in predominantly male-affected cases was evident in the two families. Twenty microsatellite markers in the HRPT2 region were typed, in addition to markers in the multiple endo...
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autosomal dominant primary hyperparathyroidism and jaw tumor syndrome associated with renal hamartomas and Cystic Kidney Disease linkage to 1q21 q32 and loss of the wild type allele in renal hamartomas
The Journal of Clinical Endocrinology and Metabolism, 1996Co-Authors: Bin Tean Teh, Hunter Heath, Filip Farnebo, U Kristoffersson, B Sundelin, John Cardinal, R Axelson, Alpha S Yap, M Epstein, D CameronAbstract:Hereditary hyperparathyroidism-jaw tumor syndrome (HPT-JT) is an autosomal dominant Disease (OMIM 145001) that has recently been mapped to chromosomal region 1q21-q32 (HRPT2). Here we report two families with HPT-JT syndrome in which adult renal hamartomas or Cystic Kidney Disease were prominent associated features, possibly representing a new phenotypic variant of the HPT-JT syndrome. In the first family, renal lesions were present in five out of six affected individuals, whereas HPT and JT were seen in four and two cases, respectively. In the second family, JT was found in three of the five affected individuals and two affected members also exhibited polyCystic Kidney Disease. The possibility of the latter cosegregating as a separate autosomal dominant gene can not be ruled out. A sex-dependent penetrance of primary HPT, resulting in predominantly male-affected cases was evident in the two families. Twenty microsatellite markers in the HRPT2 region were typed, in addition to markers in the multiple endocrine neoplasia (MEN) types 1 and 2 regions at 11q13 and 10q11. The Disease in these two kindreds was linked to five markers in the 1q21-q32 region (logarithm-of-odds scores: 3.2-4.2), whereas linkage to the MEN1 and MEN2 regions was excluded. Meiotic recombinations detected in affected individuals placed the locus telomeric of D1S215, thus narrowing the HRPT2 region from > 60 to approximately 34 centimorgans. Loss of heterozygosity was studied in seven renal hamartomas from two affected individuals in the first family, as well as in a jaw tumor and a parathyroid tumor from the second family. All renal hamartomas showed loss of heterozygosity at the 1q21-q32 region. The losses invariably involved the wild type allele derived from the unaffected parent, suggesting the inactivation of a tumor suppressor gene in this region.
E Levine - One of the best experts on this subject based on the ideXlab platform.
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acquired Cystic Kidney Disease
Radiologic Clinics of North America, 1996Co-Authors: E LevineAbstract:Abstract ACKD is characterized by the development of many fluid-filled renal cysts and sometimes neoplasms in the Kidneys of individuals with chronic renal failure but without a history of hereditary Cystic Disease. The condition is seen mainly in dialysis patients, but often begins in patients with ESRD before dialysis is started. Most patients with ACKD are asymptomatic, but the disorder may be associated with such serious complications as retroperitoneal hemorrhage and metastatic renal cell carcinoma. The diagnosis of ACKD and its complications is best achieved by CT scanning, although US and MR imaging may be useful in evaluation, particularly in patients not treated with dialysis. Cyst hemorrhage is common in ACKD and may cause flank pain and hematuria. Hemorrhagic cysts may be recognized by their CT scan, sonographic, or MR imaging features. Hemorrhagic cysts may rupture into the perinephric space causing large perinephric hematomas. These can usually be treated-conservatively. Patients with ACKD, particularly those treated with dialysis, have an increased risk of renal cell carcinoma. Renal cell carcinoma may also develop in the native Kidneys of renal transplant recipients with good graft function many years after transplantation. Annual imaging of the native Kidneys of all dialysis patients or of transplant recipients for the development of carcinoma is not justified, however, because it has not been shown to have a significant effect on patient outcome. Screening may, however, be useful in selected dialysis patients with good general medical condition and who have known risk factors for renal cell carcinoma including prolonged dialysis, large Kidneys, ACKD, and male gender. Screening of the native Kidneys of transplant recipients may be performed when they are referred for US evaluation of the renal allograft.
