19 research outputs found
Emerging evidence of a link between the polycystins and the mTOR pathways
Autosomal dominant polycystic kidney disease (ADPKD) is a genetic disease characterized by the formation of renal cysts. This disease can be caused by mutations in two genes, PKD1 and PKD2, which encode polycystin-1 (PC-1) and -2 (PC-2), respectively
Co-inheritance of a PKD1 mutation and homozygous PKD2 variant: A potential modifier in autosomal dominant polycystic kidney disease
Background: Autosomal dominant polycystic kidney disease (ADPKD), which is caused by mutations in polycystins 1 (PC1) and 2 (PC2), is one of the most commonly inherited renal diseases, affecting ∼1 : 1000 Caucasians. Materials and methods: We screened Greek ADPKD patients with the denaturing gradient gel electrophoresis (DGGE) assay and direct sequencing. Results: We identified a patient homozygous for a nucleotide change c.1445T > G, resulting in a novel homozygous substitution of the non-polar hydrophobic phenylalanine to the polar hydrophilic cysteine in exon 6 at codon 482 (p.F482C) of the PKD2 gene and a de-novo PKD1 splice-site variant IVS21-2delAG. We did not find this PKD2 variant in a screen of 280 chromosomes of healthy subjects, supporting its pathogenicity. The proband's parents did not have the PKD1 mutation. Real-time PCR of the PKD2 transcript from a skin biopsy revealed 20-fold higher expression in the patient than in a healthy subject and was higher in the patient's peripheral blood mononuclear cells (PBMCs) than in those of her heterozygote daughter and a healthy subject. The greater gene expression was also supported by Western blotting. Inner medullar collecting duct (IMCD) cells transfected with the mutant PKD2 mouse gene presented a perinuclear and diffuse cytoplasmic localization compared with the wild type ER localization. Patch-clamping of PBMCs from the p.F482C homozygous and heterozygous subjects revealed lower polycystin-2 channel function than in controls. Conclusions: We report for the first time a patient with ADPKD who is heterozygous for a de novo PKD1 variant and homozygous for a novel PKD2 mutation. © 2008 The Authors
Triptolide reduces cyst formation in a neonatal to adult transition Pkd1 model of ADPKD
Background. Autosomal dominant polycystic kidney disease (ADPKD), a major cause of end-stage renal failure, results from genetic mutation of either polycystin-1 (Pkd1) or polycystin-2 (Pkd2). In order to develop novel therapies to treat the advancement of disease progression, numerous rodent models of different genetic backgrounds are available to study cyst development
Molecular architecture of potassium chloride co-transporter KCC2
International audienc
The Na+-K+-2Cl- cotransporter and the osmotic stress response in a model salt transport epithelium.
Epithelia are physiologically exposed to osmotic stress resulting in alteration
of cell volume in several aspects of their functioning; therefore, the activation
of ‘emergency’ systems of rapid cell volume regulation is fundamental in
their physiology. In this review, the physiological response to osmotic stress,
particularly hypertonic stress, was described in a salt-transporting epithelium,
the intestine of the euryhaline teleost European eel. This epithelium is
physiologically exposed to changes in extracellular osmolarity and represents
a good physiological model for functional studies on cellular volume regulation,
permitting the study of volume regulated ion transport mechanisms in
a native tissue. An absorptive form of the cotransporter, homologue of the
renal NKCC2, localized on the apical membrane, was found in the intestine
of the euryhaline teleost European eel. This cotransporter accounts for the
luminal uptake of Cl); it operates in series with a basolateral Cl) conductance
and presumably a basolateral electroneutral KCl cotransport and in
parallel with a luminal K+ conductance. The ion transport model described
for eel intestine, based on the operation of an absorptive luminal Na+–K+–
2Cl), is basically the same as the model that has been proposed for the thick
ascending limb (cTAL) of the mammalian renal cortex. This paper focuses on
the role of Na+–K+–2Cl) cotransport in the responses to hypertonic stress in
the eel intestine and the role of cytoskeleton (either actin-based or tubulin
based) is discussed