Epitope-Tagged Pkhd1 Tracks the Processing, Secretion, and Localization of Fibrocystin

Bakeberg, Jason L.; Tammachote, Rachaneekorn; Woollard, John R.; Hogan, Marie C.; Tuan, Han Fang; Li, Ming; Deursen, Jan M. van; Wu, Yanhong; Huang, Bing; Torres, Vicente E.; Harris, Peter C.; Ward, Christopher J.

doi:10.1681/asn.2010111173

Cited by 71 publications

(109 citation statements)

References 27 publications

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“…The targeting construct was electroporated into 129/Sv ESCs by the Mayo Gene Targeting Core as previously described (104). Successful HR was confirmed by Southern blotting using a 5′ (2.9 kb; exon 15) and 3′ probe (2.0 kb; exons 36-46; Figure 1A) and 1.5 μg of ESC DNA digested with either BspHI (5′ probe) or MfeI (3′ probe) ( Figure 1A).…”

Section: Methodsmentioning

confidence: 99%

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Functional polycystin-1 dosage governs autosomal dominant polycystic kidney disease severity

et al. 2012

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Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations to PKD1 or PKD2, triggering progressive cystogenesis and typically leading to end-stage renal disease in midlife. The phenotypic spectrum, however, ranges from in utero onset to adequate renal function at old age. Recent patient data suggest that the disease is dosage dependent, where incompletely penetrant alleles influence disease severity. Here, we have developed a knockin mouse model matching a likely disease variant, PKD1 p.R3277C (RC), and have proved that its functionally hypomorphic nature modifies the ADPKD phenotype. While Pkd1 +/null mice are normal, Pkd1 RC/null mice have rapidly progressive disease, and Pkd1 RC/RC animals develop gradual cystogenesis. These models effectively mimic the pathophysiological features of in utero-onset and typical ADPKD, respectively, correlating the level of functional Pkd1 product with disease severity, highlighting the dosage dependence of cystogenesis. Additionally, molecular analyses identified p.R3277C as a temperature-sensitive folding/ trafficking mutant, and length defects in collecting duct primary cilia, the organelle central to PKD pathogenesis, were clearly detected for the first time to our knowledge in PKD1. Altogether, this study highlights the role that in trans variants at the disease locus can play in phenotypic modification of dominant diseases and provides a truly orthologous PKD1 model, optimal for therapeutic testing.

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Section: Methodsmentioning

confidence: 99%

“…Urinary ELVs were isolated as described previously (104). Three male and three female WT or Pkd1 RC/RC animals were placed in metabolic cages for 12 hours to collect 10 ml urine (overall experimental, n = 4).…”

Section: Methodsmentioning

confidence: 99%

Functional polycystin-1 dosage governs autosomal dominant polycystic kidney disease severity

et al. 2012

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“…No glycoproteomic data are available indicating N-glycosylation of PKHD1L1. However, its paralog fibrocystin (polycystic and hepatic disease 1 (PKHD1)) was known to be highly N-glycosylated (90). Fibrocystin-like proteins are proposed to be evolutionary ancestors of fibrocystin and thus exhibit many structural similarities (91)(92)(93).…”

Section: Table I Relative Quantification Of the N-glycans Found On Ccmentioning

confidence: 99%

Exploring the N-glycosylation Pathway in Chlamydomonas reinhardtii Unravels Novel Complex Structures

Mathieu‐Rivet

Scholz

Arias

et al. 2013

Molecular & Cellular Proteomics

142

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Chlamydomonas reinhardtii is a green unicellular eukaryotic model organism for studying relevant biological and biotechnological questions. The availability of genomic resources and the growing interest in C. reinhardtii as an emerging cell factory for the industrial production of biopharmaceuticals require an in-depth analysis of protein N-glycosylation in this organism. Accordingly, we used a comprehensive approach including genomic, glycomic, and glycoproteomic techniques to unravel the N-glycosylation pathway of C. reinhardtii. Using mass-spectrometry-based approaches, we found that both endogenous soluble and membrane-bound proteins carry predominantly oligomannosides ranging from Man-2 to Man-5. In addition, minor complex N-linked glycans were identified as being composed of partially 6-Omethylated Man-3 to Man-5 carrying one or two xylose residues. These findings were supported by results from a glycoproteomic approach that led to the identification of 86 glycoproteins. Here, a combination of in-source collision-induced dissodiation (CID) for glycan fragmentation followed by mass tag-triggered CID for peptide sequencing and PNGase F treatment of glycopeptides in the presence of 18 O-labeled water in conjunction with CID mass spectrometric analyses were employed. In conclusion, our data support the notion that the biosynthesis and maturation of N-linked glycans in the endoplasmic reticulum and Golgi apparatus occur via a GnT I-independent pathway yielding novel complex N-linked glycans that maturate differently from their counterparts in land plants. Molecular & Cellular

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“…Instead, differences in intrinsic susceptibility to the development of PKD between rats and mice may be a contributory factor. In this regard, it is telling that the PCK rat exhibits renal cysts at or soon after birth (13), whereas most Pkhd1 knockout mice only develop renal cysts at an advanced age or not at all (3,5,6,15,31,32). The renal phenotype of Pkd1 or Pkd2 heterozygous knockout mice is similarly normal or very mild; unfortunately, no Pkd1 or Pkd2 rat model currently exists (21).…”

Section: Pkd2mentioning

confidence: 99%

Effects of hydration in rats and mice with polycystic kidney disease

Hopp

Wang

et al. 2015

American Journal of Physiology-Renal Physiology

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Hopp K, Wang X, Ye H, Irazabal MV, Harris PC, Torres VE. Effects of hydration in rats and mice with polycystic kidney disease. Am J Physiol Renal Physiol 308: F261-F266, 2015. First published December 10, 2014 doi:10.1152/ajprenal.00345.2014.-Vasopressin and V2 receptor signaling promote polycystic kidney disease (PKD) progression, raising the question whether suppression of vasopressin release through enhanced hydration can delay disease advancement. Enhanced hydration by adding 5% glucose to the drinking water has proven protective in a rat model orthologous to autosomal recessive PKD. We wanted to exclude a glucose effect and explore the influence of enhanced hydration in a mouse model orthologous to autosomal dominant PKD. PCK rats were assigned to normal water intake (NWI) or high water intake (HWI) groups achieved by feeding a hydrated agar diet (HWI-agar) or by adding 5% glucose to the drinking water (HWI-glucose), with the latter group used to recapitulate previously published results. Homozygous Pkd1 R3277C (Pkd1 RC/RC ) mice were assigned to NWI and HWI-agar groups. To evaluate the effectiveness of HWI, kidney weight and histomorphometry were assessed, and urine vasopressin, renal cAMP levels, and phosphodiesterase activities were measured. HWI-agar, like HWI-glucose, reduced urine vasopressin, renal cAMP levels, and PKD severity in PCK rats but not in Pkd1 RC/RC mice. Compared with rat kidneys, mouse kidneys had higher phosphodiesterase activity and lower cAMP levels and were less sensitive to the cystogenic effect of 1-deamino-8-D-arginine vasopressin, as previously shown for Pkd1 RC/RC mice and confirmed here in Pkd2 WS25/Ϫ mice. We conclude that the effect of enhanced hydration in rat and mouse models of PKD differs. More powerful suppression of V2 receptor-mediated signaling than achievable by enhanced hydration alone may be necessary to affect the development of PKD in mouse models. polycystic kidney disease; vasopressin; cAMP; cyclic nucleotide phosphodiesterase; hydration POLYCYSTIC KIDNEY DISEASES (PKDs) are characterized by the development and growth of cysts arising from renal tubules and associated with enlargement of the kidneys and destruction of the renal parenchyma. Autosomal dominant PKD (AD-PKD), the fourth leading cause of end-stage kidney disease in adults, is caused by mutations to either of two genes, PKD1 or PKD2. Autosomal recessive PKD (ARPKD), an important cause of end-stage renal disease and mortality in infants and children, is caused by mutations to polycystic kidney and hepatic disease 1 (PKHD1) (9,23).A large body of evidence indicates that vasopressin and V2 receptor signaling promote the progression of PKD via cAMP and PKA (22). Administration of the V2 receptor agonist 1-deamino-8-D-arginine vasopressin (DDAVP) aggravates the disease in orthologous models of ARPKD and PKD1 (10,28). Genetic elimination of circulating vasopressin markedly inhibits the development of PKD in PCK rats, an effect that was reversed by the administration of DDAVP (28). Treatment with select...

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Epitope-Tagged Pkhd1 Tracks the Processing, Secretion, and Localization of Fibrocystin

Cited by 71 publications

References 27 publications

Functional polycystin-1 dosage governs autosomal dominant polycystic kidney disease severity

Functional polycystin-1 dosage governs autosomal dominant polycystic kidney disease severity

Exploring the N-glycosylation Pathway in Chlamydomonas reinhardtii Unravels Novel Complex Structures

Effects of hydration in rats and mice with polycystic kidney disease

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