A new method for studying human polycystic kidney disease epithelia in culture

Wilson, Patricia D.; Schrier, Robert W.; Breckon, R.; Gabow, Patricia A.

doi:10.1038/ki.1986.194

Cited by 108 publications

(47 citation statements)

References 22 publications

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“…The mechanism behind this decreased urine concentrating capacity is not known, but it is suggested to have a renal origin. The impaired ability to reabsorb water could be secondary to cystinduced abnormality in renal architecture, leading to an impaired medullary osmotic gradient (15) or to insensitivity to AVP (e.g., due to a receptor defect) (4,16). Theoretically, a lower renal concentrating capacity could also have a central cause (i.e., impaired AVP release by the pituitary gland).…”

Section: Introductionmentioning

confidence: 99%

Vasopressin, Copeptin, and Renal Concentrating Capacity in Patients with Autosomal Dominant Polycystic Kidney Disease without Renal Impairment

Zittema¹,

Boertien²,

Beek

et al. 2012

Clinical Journal of the American Society of Nephrology

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SummaryBackground and objectives Autosomal dominant polycystic kidney disease (ADPKD) is the most prevalent hereditary renal disease, characterized by cyst formation in the kidneys leading to end stage kidney failure. It is clinically acknowledged that ADPKD patients have impaired urine concentrating capacity, but the mechanism behind this observation is unknown.Design, setting, participants, & measurements Fifteen ADPKD patients (estimated GFR $60 ml/min per 1.73 m 2 ) and 15 age-and sex-matched healthy controls underwent a standard prolonged water deprivation test in which urine and plasma osmolality, vasopressin, and copeptin were measured. The effect of a synthetic vasopressin analog (desmopressin) injected at the moment of maximal urine concentrating capacity was also studied.Results After 14 hours of water deprivation, ADPKD patients tended to have higher plasma osmolality (P=0.07) and significantly higher vasopressin and copeptin levels (both P,0.05), whereas urine osmolality was similar in ADPKD patients and controls (710 versus 742 mOsmol/kg; P=0.61). Maximal urine concentrating capacity was lower in ADPKD patients (758 versus 915 mOsmol/kg in controls; P,0.001). At maximal urine concentrating capacity, plasma osmolality, vasopressin, and copeptin levels were significantly higher in ADPKD patients. The median increase in urine osmolality after desmopressin administration in ADPKD patients was less than in healthy controls.Conclusions Already early in their disease, ADPKD patients have impaired maximal urine concentrating capacity brought out upon dehydration, with no evidence of impaired hypothalamic response. To maintain fluid balance, vasopressin concentration increases, which is hypothesized to play a role in ADPKD disease progression.

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Section: Introductionmentioning

confidence: 99%

Vasopressin, Copeptin, and Renal Concentrating Capacity in Patients with Autosomal Dominant Polycystic Kidney Disease without Renal Impairment

Zittema¹,

Boertien²,

Beek

et al. 2012

Clinical Journal of the American Society of Nephrology

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“…16,17 Primary cells taken from nephrectomized ADPKD kidneys have been linked to various epithelial cell phenotypes, but because these cells are derived from kidneys with advanced disease, it remains unclear whether these characteristics represent primary defects central to PKD etiology or secondary consequences of injury or dedifferentiation. 6,[18][19][20][21] A powerful new technology, induced pluripotent stem (iPS) cells are adult somatic cells which have been reprogrammed into an embryonic pluripotent state. 22,23 The result is a next generation cell culture model that can differentiate into diverse cell types and complex tissues for the purposes of regenerative therapies or investigating disease.…”

mentioning

confidence: 99%

Reduced Ciliary Polycystin-2 in Induced Pluripotent Stem Cells from Polycystic Kidney Disease Patients with PKD1 Mutations

Freedman

Lam

Sundsbak

et al. 2013

Journal of the American Society of Nephrology

104

124

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Heterozygous mutations in PKD1 or PKD2, which encode polycystin-1 (PC1) and polycystin-2 (PC2), respectively, cause autosomal dominant PKD (ADPKD), whereas mutations in PKHD1, which encodes fibrocystin/ polyductin (FPC), cause autosomal recessive PKD (ARPKD). However, the relationship between these proteins and the pathogenesis of PKD remains unclear. To model PKD in human cells, we established induced pluripotent stem (iPS) cell lines from fibroblasts of three ADPKD and two ARPKD patients. Genetic sequencing revealed unique heterozygous mutations in PKD1 of the parental ADPKD fibroblasts but no pathogenic mutations in PKD2. Undifferentiated PKD iPS cells, control iPS cells, and embryonic stem cells elaborated primary cilia and expressed PC1, PC2, and FPC at similar levels, and PKD and control iPS cells exhibited comparable rates of proliferation, apoptosis, and ciliogenesis. However, ADPKD iPS cells as well as somatic epithelial cells and hepatoblasts/biliary precursors differentiated from these cells expressed lower levels of PC2 at the cilium. Additional sequencing confirmed the retention of PKD1 heterozygous mutations in iPS cell lines from two patients but identified possible loss of heterozygosity in iPS cell lines from one patient. Furthermore, ectopic expression of wild-type PC1 in ADPKD iPS-derived hepatoblasts rescued ciliary PC2 protein expression levels, and overexpression of PC1 but not a carboxy-terminal truncation mutant increased ciliary PC2 expression levels in mouse kidney cells. Taken together, these results suggest that PC1 regulates ciliary PC2 protein expression levels and support the use of PKD iPS cells for investigating disease pathophysiology.

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“…Also, they observed that nearly every cyst had an abnormal basement membrane. In 1986, Patricia Wilson and her colleagues observed that human PKD epithelial cells in culture exhibited an extremely abnormal basement membrane morphology consisting of some banded collagen and numerous unique blebs or spheroids (Wilson et al, 1986). These blebs stained with ruthenium red, suggesting a proteoglycan component.…”

Section: Early Observations Of Ecm Abnormalities In Pkdmentioning

confidence: 99%

Extracellular Matrix Abnormalities in Polycystic Kidney Disease

Vijayakumar¹

2012

Novel Insights on Chronic Kidney Disease, Acute Kidney Injury and Polycystic Kidney Disease

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A new method for studying human polycystic kidney disease epithelia in culture

Cited by 108 publications

References 22 publications

Vasopressin, Copeptin, and Renal Concentrating Capacity in Patients with Autosomal Dominant Polycystic Kidney Disease without Renal Impairment

Vasopressin, Copeptin, and Renal Concentrating Capacity in Patients with Autosomal Dominant Polycystic Kidney Disease without Renal Impairment

Reduced Ciliary Polycystin-2 in Induced Pluripotent Stem Cells from Polycystic Kidney Disease Patients with PKD1 Mutations

Extracellular Matrix Abnormalities in Polycystic Kidney Disease

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