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  • American Physiological Society  (7)
  • Yoder, Bradley K.  (7)
  • 1
    Online Resource
    Online Resource
    Deletion of airway cilia results in noninflammatory bronchiectasis and hyperreactive airways
    American Physiological Society ; 2014
    In:  American Journal of Physiology-Lung Cellular and Molecular Physiology Vol. 306, No. 2 ( 2014-01-15), p. L162-L169
    Details
    In: American Journal of Physiology-Lung Cellular and Molecular Physiology, American Physiological Society, Vol. 306, No. 2 ( 2014-01-15), p. L162-L169
    Abstract: The mechanisms for the development of bronchiectasis and airway hyperreactivity have not been fully elucidated. Although genetic, acquired diseases and environmental influences may play a role, it is also possible that motile cilia can influence this disease process. We hypothesized that deletion of a key intraflagellar transport molecule, IFT88, in mature mice causes loss of cilia, resulting in airway remodeling. Airway cilia were deleted by knockout of IFT88, and airway remodeling and pulmonary function were evaluated. In IFT88 − mice there was a substantial loss of airway cilia on respiratory epithelium. Three months after the deletion of cilia, there was clear evidence for bronchial remodeling that was not associated with inflammation or apparent defects in mucus clearance. There was evidence for airway epithelial cell hypertrophy and hyperplasia. IFT88 − mice exhibited increased airway reactivity to a methacholine challenge and decreased ciliary beat frequency in the few remaining cells that possessed cilia. With deletion of respiratory cilia there was a marked increase in the number of club cells as seen by scanning electron microscopy. We suggest that airway remodeling may be exacerbated by the presence of club cells, since these cells are involved in airway repair. Club cells may be prevented from differentiating into respiratory epithelial cells because of a lack of IFT88 protein that is necessary to form a single nonmotile cilium. This monocilium is a prerequisite for these progenitor cells to transition into respiratory epithelial cells. In conclusion, motile cilia may play an important role in controlling airway structure and function.
    Type of Medium: Online Resource
    ISSN: 1040-0605 , 1522-1504
    URL: Article
    DOI: 10.1152/ajplung.00095.2013
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2014
    detail.hit.zdb_id: 1013184-X
    detail.hit.zdb_id: 1477300-4
    SSG: 12
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  • 2
    Online Resource
    Online Resource
    Truncating PKHD1 and PKD2 mutations alter energy metabolism
    American Physiological Society ; 2019
    In:  American Journal of Physiology-Renal Physiology Vol. 316, No. 3 ( 2019-03-01), p. F414-F425
    Details
    In: American Journal of Physiology-Renal Physiology, American Physiological Society, Vol. 316, No. 3 ( 2019-03-01), p. F414-F425
    Abstract: Deficiency in polycystin 1 triggers specific changes in energy metabolism. To determine whether defects in other human cystoproteins have similar effects, we studied extracellular acidification and glucose metabolism in human embryonic kidney (HEK-293) cell lines with polycystic kidney and hepatic disease 1 ( PKHD1) and polycystic kidney disease (PKD) 2 ( PKD2) truncating defects along multiple sites of truncating mutations found in patients with autosomal recessive and dominant PKDs. While neither the PKHD1 or PKD2 gene mutations nor their position enhanced cell proliferation rate in our cell line models, truncating mutations in these genes progressively increased overall extracellular acidification over time ( P 〈 0.001 for PKHD1 and PKD2 mutations). PKHD1 mutations increased nonglycolytic acidification rate (1.19 vs. 1.03, P = 0.002), consistent with an increase in tricarboxylic acid cycle activity or breakdown of intracellular glycogen. In addition, they increased basal and ATP-linked oxygen consumption rates [7.59 vs. 5.42 ( P = 0.015) and 4.55 vs. 2.98 ( P = 0.004)]. The PKHD1 and PKD2 mutations also altered mitochondrial morphology, resembling the effects of polycystin 1 deficiency. Together, these data suggest that defects in major PKD genes trigger changes in mitochondrial energy metabolism. After validation in in vivo models, these initial observations would indicate potential benefits of targeting energy metabolism in the treatment of PKDs.
    Type of Medium: Online Resource
    ISSN: 1931-857X , 1522-1466
    URL: Article
    DOI: 10.1152/ajprenal.00167.2018
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2019
    detail.hit.zdb_id: 1477287-5
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  • 3
    Online Resource
    Online Resource
    Heterozygous Pkhd1 C642* mice develop cystic liver disease and proximal tubule ectasia that mimics radiographic signs of medullary sponge kidney
    American Physiological Society ; 2019
    In:  American Journal of Physiology-Renal Physiology Vol. 316, No. 3 ( 2019-03-01), p. F463-F472
    Details
    In: American Journal of Physiology-Renal Physiology, American Physiological Society, Vol. 316, No. 3 ( 2019-03-01), p. F463-F472
    Abstract: Heterozygosity for human polycystic kidney and hepatic disease 1 ( PKHD1) mutations was recently associated with cystic liver disease and radiographic findings resembling medullary sponge kidney (MSK). However, the relevance of these associations has been tempered by a lack of cystic liver or renal disease in heterozygous mice carrying Pkhd1 gene trap or exon deletions. To determine whether heterozygosity for a smaller Pkhd1 defect can trigger cystic renal disease in mice, we generated and characterized mice with the predicted truncating Pkhd1 C642* mutation in a region corresponding to the middle of exon 20 cluster of five truncating human mutations (between PKHD1 G617fs and PKHD1 G644* ). Mouse heterozygotes or homozygotes for the Pkhd1 C642* mutation did not have noticeable liver or renal abnormalities on magnetic resonance images during their first weeks of life. However, when aged to ~1.5 yr, the Pkhd1 C642* heterozygotes developed prominent cystic liver changes; tissue analyses revealed biliary cysts and increased number of bile ducts without signs of congenital hepatic fibrosis-like portal field inflammation and fibrosis that was seen in Pkhd1 C642* homozygotes. Interestingly, aged female Pkhd1 C642* heterozygotes, as well as homozygotes, developed radiographic changes resembling MSK. However, these changes correspond to proximal tubule ectasia, not an MSK-associated collecting duct ectasia. In summary, by demonstrating that cystic liver and kidney abnormalities are triggered by heterozygosity for the Pkhd1 C642* mutation, we provide important validation for relevant human association studies. Together, these investigations indicate that PKHD1 mutation heterozygosity (predicted frequency 1 in 70 individuals) is an important underlying cause of cystic liver disorders and MSK-like manifestations in a human population.
    Type of Medium: Online Resource
    ISSN: 1931-857X , 1522-1466
    URL: Article
    DOI: 10.1152/ajprenal.00181.2018
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2019
    detail.hit.zdb_id: 1477287-5
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  • 4
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    Online Resource
    Heightened epithelial Na + channel-mediated Na + absorption in a murine polycystic kidney disease model epithelium lacking apical monocilia
    American Physiological Society ; 2006
    In:  American Journal of Physiology-Cell Physiology Vol. 290, No. 4 ( 2006-04), p. C952-C963
    Details
    In: American Journal of Physiology-Cell Physiology, American Physiological Society, Vol. 290, No. 4 ( 2006-04), p. C952-C963
    Abstract: The Tg737° rpk autosomal recessive polycystic kidney disease (ARPKD) mouse carries a hypomorphic mutation in the Tg737 gene. Because of the absence of its protein product Polaris, the nonmotile primary monocilium central to the luminal membrane of ductal epithelia, such as the cortical collecting duct (CCD) principal cell (PC), is malformed. Although the functions of the renal monocilium remain elusive, primary monocilia or flagella on neurons act as sensory organelles. Thus we hypothesized that the PC monocilium functions as a cellular sensor. To test this hypothesis, we assessed the contribution of Polaris and cilium structure and function to renal epithelial ion transport electrophysiology. Properties of Tg737° rpk mutant CCD PC clones were compared with clones genetically rescued with wild-type Tg737 cDNA. All cells were grown as polarized cell monolayers with similarly high transepithelial resistance on permeable filter supports. Three- to fourfold elevated transepithelial voltage ( V te ) and short-circuit current ( I sc ) were measured in mutant orpk monolayers vs. rescued controls. Pharmacological and cell biological examination of this enhanced electrical end point in mutant monolayers revealed that epithelial Na + channels (ENaCs) were upregulated. Amiloride, ENaC-selective amiloride analogs (benzamil and phenamil), and protease inhibitors (aprotinin and leupeptin) attenuated heightened V te and I sc . Higher concentrations of additional amiloride analogs (ethylisopropylamiloride and dimethylamiloride) also revealed inhibition of V te . Cell culture requirements and manipulations were also consistent with heightened ENaC expression and function. Together, these data suggest that ENaC expression and/or function are upregulated in the luminal membrane of mutant, cilium-deficient orpk CCD PC monolayers vs. cilium-competent controls. When the genetic lesion causes loss or malformation of the monocilium, ENaC-driven Na + hyperabsorption may explain the rapid emergence of severe hypertension in a majority of patients with ARPKD.
    Type of Medium: Online Resource
    ISSN: 0363-6143 , 1522-1563
    URL: Article
    DOI: 10.1152/ajpcell.00339.2005
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2006
    detail.hit.zdb_id: 1477334-X
    detail.hit.zdb_id: 392098-7
    SSG: 12
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  • 5
    Online Resource
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    Primary cilia disruption differentially affects the infiltrating and resident macrophage compartment in the liver
    American Physiological Society ; 2018
    In:  American Journal of Physiology-Gastrointestinal and Liver Physiology Vol. 314, No. 6 ( 2018-06-01), p. G677-G689
    Details
    In: American Journal of Physiology-Gastrointestinal and Liver Physiology, American Physiological Society, Vol. 314, No. 6 ( 2018-06-01), p. G677-G689
    Abstract: Hepatorenal fibrocystic disease (HRFCD) is characterized by cysts in the kidney and liver with associated fibrosis and is the result of defects in proteins required for cilia function or assembly. Previous reports indicate that macrophages, mainly M2-like macrophages, contribute to HRFCD, although the origin of these cells (yolk sac-derived resident macrophages vs. bone marrow-derived infiltrating macrophages) and their contribution to the observed phenotypes are unknown. We utilize a congenital model of cilia dysfunction (IFT88 Orpk ) to study the importance of macrophages in HRFCD. Our data show a rapid expansion of the bile duct region and development of fibrosis between 2 and 4 wk of age. Immunofluorescence microscopy analysis reveals an accumulation of F4/80 + macrophages in regions exhibiting biliary hyperplasia in IFT88 Orpk mice. Flow cytometry data show that cilia dysfunction leads to an accumulation of infiltrating macrophages (CD11b hi , F4/80 lo ) and a reduction of resident macrophage (CD11b lo , F4/80 hi ) number. A majority of the infiltrating macrophages are Ly6c hi profibrogenic macrophages. Along with the accumulation of immune cells, expression of proinflammatory and profibrotic transcripts, including TGF-β, TNF-α, IL-1β, and chemokine (C-C) motif ligand 2, is increased. Quantitative RT-PCR analysis of flow-sorted cells shows enhanced expression of CCL2 in cholangiocytes and enhanced expression of VEGF-A and IL-6 in Ly6c hi macrophages. Genetic inhibition of Ly6c hi macrophage accumulation in IFT88 Orpk FVB CCR2 −/− mice reduced biliary fibrosis but did not affect epithelial expansion. Collectively, these studies suggest that biliary epithelium with defects in primary cilia preferentially recruits Ly6c hi infiltrating macrophages, which promote fibrotic progression in HRFCD pathogenesis. NEW & NOTEWORTHY These studies are the first to address the contribution of the infiltrating and resident macrophage niche during progression of hepatorenal fibrocystic disease (HRFCD). We show that the number of infiltrating macrophages is significantly upregulated in HRFCD mouse models. Finally, we show that prevention of Ly6c hi infiltrating macrophage accumulation significantly reduces biliary fibrosis, but not biliary hyperplasia, suggesting that this population may be responsible for the fibrotic progression of the disease in HRFCD patients.
    Type of Medium: Online Resource
    ISSN: 0193-1857 , 1522-1547
    URL: Article
    DOI: 10.1152/ajpgi.00381.2017
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2018
    detail.hit.zdb_id: 1477329-6
    detail.hit.zdb_id: 603840-2
    SSG: 12
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  • 6
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    Polaris, a protein disrupted in orpk mutant mice, is required for assembly of renal cilium
    American Physiological Society ; 2002
    In:  American Journal of Physiology-Renal Physiology Vol. 282, No. 3 ( 2002-03-01), p. F541-F552
    Details
    In: American Journal of Physiology-Renal Physiology, American Physiological Society, Vol. 282, No. 3 ( 2002-03-01), p. F541-F552
    Abstract: Cilia are organelles that play diverse roles, from fluid movement to sensory reception. Polaris, a protein associated with cystic kidney disease in Tg737° rpk mice, functions in a ciliogenic pathway. Here, we explore the role of polaris in primary cilia on Madin-Darby canine kidney cells. The results indicate that polaris localization and solubility change dramatically during cilia formation. These changes correlate with the formation of basal bodies and large protein rafts at the apical surface of the epithelia. A cortical collecting duct cell line has been derived from mice with a mutation in the Tg737 gene. These cells do not develop normal cilia, which can be corrected by reexpression of the wild-type Tg737 gene. These data suggest that the primary cilia are important for normal renal function and/or development and that the ciliary defect may be a contributing factor to the cystic disease in Tg737° rpk mice. Further characterization of these cells will be important in elucidating the physiological role of renal cilia and in determining their relationship to cystic disease.
    Type of Medium: Online Resource
    ISSN: 1931-857X , 1522-1466
    URL: Article
    DOI: 10.1152/ajprenal.00273.2001
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2002
    detail.hit.zdb_id: 1477287-5
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  • 7
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    Online Resource
    Kidney resident macrophages in the rat have minimal turnover and replacement by blood monocytes
    American Physiological Society ; 2021
    In:  American Journal of Physiology-Renal Physiology Vol. 321, No. 2 ( 2021-08-01), p. F162-F169
    Details
    In: American Journal of Physiology-Renal Physiology, American Physiological Society, Vol. 321, No. 2 ( 2021-08-01), p. F162-F169
    Abstract: Kidney resident macrophages (KRMs) are involved in maintaining renal homeostasis and in controlling the pathological outcome of acute kidney injury and cystic kidney disease in mice. In adult mice, KRMs maintain their population through self-renewal with little or no input from the peripheral blood. Despite recent data suggesting that a transcriptionally similar population of KRM-like cells is present across species, the idea that they are self-renewing and minimally dependent on peripheral blood input in other species has yet to be proven due to the lack of an appropriate model and cross-species expression markers. In this study, we used our recently identified cross-species KRM cell surface markers and parabiosis surgery in inbred Lewis rats to determine if rat KRMs are maintained independent of peripheral blood input, similar to their mouse counterparts. Flow cytometry analysis indicated that parabiosis surgery in the rat results in the establishment of chimerism of T/B cells, neutrophils, and monocyte-derived infiltrating macrophages in the blood, spleen, and kidney 3 wk after parabiosis surgery. Analysis of KRMs using the cell surface markers CD81 and C1q indicated that these cells have minimal chimerism and, therefore, receive little input from the peripheral blood. These data indicate that KRM properties are conserved in at least two different species. NEW & NOTEWORTHY In this report, we performed parabiosis surgery on inbred Lewis rats and showed that rat kidney resident macrophages (KRMs), identified using our novel cross-species markers, are minimally dependent on peripheral blood input. Thus, for the first time, to our knowledge, we confirm that a hallmark of mouse KRMs is also present in KRMs isolated from another species.
    Type of Medium: Online Resource
    ISSN: 1931-857X , 1522-1466
    URL: Article
    DOI: 10.1152/ajprenal.00129.2021
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2021
    detail.hit.zdb_id: 1477287-5
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