https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(07)60601-1.pdf

Autosomal dominant polycystic kidney disease

The Vertebrate Primary Cilium in Development, Homeostasis, and Disease

A number of inherited disorders result in renal cyst development. The most common form, autosomal dominant polycystic kidney disease (ADPKD), is a disorder most often diagnosed in adults and caused by mutation in PKD1 or PKD2. The PKD1 protein, polycystin-1, is a large receptor-like protein, whereas polycystin-2 is a transient receptor potential channel. The polycystin complex localizes to primary cilia and may act as a mechanosensor essential for maintaining the differentiated state of epithelia lining tubules in the kidney and biliary tract. Elucidation of defective cellular processes has highlighted potential therapies, some of which are now being tested in clinical trials. ARPKD is the neonatal form of PKD and is associated with enlarged kidneys and biliary dysgenesis. The disease phenotype is highly variable, ranging from neonatal death to later presentation with minimal kidney disease. ARPKD is caused by mutation in PKHD1, and two truncating mutations are associated with neonatal lethality. The ARPKD protein, fibrocystin, is localized to cilia/basal body and complexes with polycystin-2. Rare, syndromic forms of PKD also include defects of the eye, central nervous system, digits, and/or neural tube and highlight the role of cilia and pathways such as Wnt and Hh in their pathogenesis. 

pdf/polycystic-kidney-disease-186vjzytyx.pdf

Polycystic Kidney Disease

Cystic kidneys are common causes of end-stage renal disease, both in children and in adults. Autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD) are cilia-related disorders and the two main forms of monogenic cystic kidney diseases. ADPKD is a common disease that mostly presents in adults, whereas ARPKD is a rarer and often more severe form of polycystic kidney disease (PKD) that usually presents perinatally or in early childhood. Cell biological and clinical research approaches have expanded our knowledge of the pathogenesis of ADPKD and ARPKD and revealed some mechanistic overlap between them. A reduced 'dosage' of PKD proteins is thought to disturb cell homeostasis and converging signalling pathways, such as Ca2+, cAMP, mechanistic target of rapamycin, WNT, vascular endothelial growth factor and Hippo signalling, and could explain the more severe clinical course in some patients with PKD. Genetic diagnosis might benefit families and improve the clinical management of patients, which might be enhanced even further with emerging therapeutic options. However, many important questions about the pathogenesis of PKD remain. In this Primer, we provide an overview of the current knowledge of PKD and its treatment.

Polycystic kidney disease.

Fertilization calcium waves are introduced, and the evidence from which we can infer general mechanisms of these waves is presented. The two main classes of hypotheses put forward to explain the ge...

/pdf/calcium-at-fertilization-and-in-early-development-4f8xabt5ha.pdf

Calcium at fertilization and in early development.

FPC (fibrocystin or polyductin) is a single transmembrane receptor-like protein, responsible for the human autosomal recessive polycystic kidney disease (ARPKD). It was recently proposed that FPC undergoes a Notch-like cleavage and subsequently the cleaved carboxy(C)-terminal fragment translocates to the nucleus. To study the functions of the isolated Ctail, we expressed the intracellular domain of human FPC (hICD) in renal epithelial cells. By 3-dimensional (3D) tubulogenesis assay, we found that in contrast to tubule-like structures formed from control cells, hICD-expressing cells exclusively formed cyst-like structures. By western blotting, we showed that the Akt/mTOR pathway, indicated by increased phosphorylation of Akt at serine 473 and S6 kinase 1 at threonine 389, was constitutively activated in hICD-expressing cells, similar to that in FPC knockdown cells and ARPKD kidneys. Moreover, application of mTOR inhibitor rapamycin reduced the size of the cystlike structures formed by hICD-expressing cells. Application of either LY294002 or wortmannin inhibited the activation of both S6K1 and Akt. Expression of full-length FPC inhibited the activation of S6 and S6 kinase whereas co-expression of hICD with full-length FPC antagonized the inhibitory effect of full-length FPC on mTOR. Taken together, we propose that FPC modulates the PI3K/Akt/mTOR pathway and the cleaved C-tail regulates the function of the full-length protein.

/pdf/the-cytoplasmic-tail-of-fpc-antagonizes-the-full-length-4186mgfq2t.pdf

The Cytoplasmic Tail of FPC Antagonizes the Full-Length Protein in the Regulation of mTOR Pathway

Planar cell polarity (PCP), a process of coordinated alignment of cell polarity across the tissue plane, may contribute to the repair of renal tubules after kidney injury. Intu is a key effector protein of PCP. Herein, conditional knockout (KO) mouse models that ablate Intu specifically from kidney tubules (Intu KO) were established. Intu KO mice and wild-type littermates were subjected to unilateral renal ischemia/reperfusion injury (IRI) or unilateral ureteral obstruction. Kidney repair was evaluated by histologic, biochemical, and immunohistochemical analyses. In vitro, scratch wound healing was examined in Intu-knockdown and control renal tubular cells. Ablation of Intu in renal tubules delayed kidney repair and ameliorated renal fibrosis after renal IRI. Intu KO mice had less renal fibrosis during unilateral ureteral obstruction. Mechanistically, Intu KO kidneys had less senescence but higher levels of cell proliferation and apoptosis during kidney repair after renal IRI. In vitro, Intu knockdown suppressed scratch wound healing in renal tubular cells, accompanied by the abnormality of centrosome orientation. Together, the results provide the first evidence for the involvement of PCP in tubular repair after kidney injury, shedding light on new strategies for improving kidney repair and recovery. 

Deficiency of the planar cell polarity protein intu delays kidney repair and suppresses renal fibrosis after acute kidney injury.

Almost every cell in the kidney, including renal tubular epithelial cells, has a primary cilium, which is a membrane-bound, hair-like structure protruding from the cellular surface. Dysfunction of primary cilia has been linked to a wide spectrum of human genetic diseases, termed ciliopathies. Planar cell polarity (PCP) refers to the coordinated alignment of cells along the cell sheet or tissue plane, a fundamental process in embryo development and organogenesis. Interestingly, there is evidence that primary cilium and PCP are interconnected. However, very limited is known about the involvement of cilia and PCP in kidney injury and repair. By using cell and mouse models, we have demonstrated a protective role of primary cilia in acute kidney injury. Mechanistically, we unveiled a reciprocal promoting relationship between cilia and autophagy in kidney tubular cells, and, accordingly, cilia may protect tubular cells by enhancing autophagy. Our recent studies further demonstrated that PCP dysfunction exaggerates acute kidney injury and may also contribute to maladaptive kidney repair after acute kidney injury. These findings provide a novel dimension to further understanding kidney injury and repair from the standpoint of cell biology.

From Primary Cilia and Planar Cell Polarity to Kidney Injury and Repair.

. Background: Intu is an effector protein of the planar cell polarity network that is essential for embryonic development and maintenance of normal organ functions. It was recently demonstrated that Intu plays a protective role in renal ischemia/reperfusion injury via interacting partner Stat1. However, the role of Intu in kidney repair and fibrosis remains unknown. Methods: We have established an inducible Intu knockout mouse model that was exposed to doxycycline to ablate Intu specifically from kidney tubules (iRT-Intu-KO). iRT-Intu-KO mice and wild-type littermates were subjected to unilateral renal ischemia/ reperfusion or ureteral obstruction injury. Kidney repair/recovery was evaluated by histological, biochemical, immunohistochemical and immunofluorescence approaches. In vitro, we examined Intu-knockdown proximal tubular cells. Results: We found that ablation of Intu in renal tubules delayed kidney recovery and ameliorated renal fibrosis after renal ischemia/reperfusion injury. These mice also had less renal fibrosis during unilateral ureteral obstruction. We further found that senescence was suppressed while cell proliferation was increased in Intu knockout kidneys following renal ischemia/reperfusion injury. In cultured renal tubular cells, knockdown of Intu inhibited cell migration, accompanied by the abnormality of centrosome orientation. Conclusions: Knockout of Intu suppressed kidney recovery and weakened fibrosis, associated with centrosome orientation abnormality and senescence inhibition. These findings suggest that planar cell polarity may contribute to tubular repair after kidney injury, shedding light on new strategies for improving kidney repair and recovery. Funding:

Intu Deficiency in Renal Tubules Delays Kidney Repair yet Suppresses Renal Fibrosis After Kidney Injury

Autosomal recessive polycystic kidney disease (ARPKD) is a significant hereditary renal disease occurring in infancy and childhood, which presents with greatly enlarged echogenic kidneys, ultimately leading to renal insufficiency and end-stage renal disease. ARPKD is caused by mutations in a single gene PKHD1, which encodes fibrocystin/polyductin (FPC), a large single transmembrane protein generally known to be on the primary cilium, basal body and plasma membrane. Here, using our newly generated antibody raised against the entire C-terminal intracellular cytoplasmic domain (ICD) of FPC, as well as our previously well-characterized antibody against a peptide of ICD, we report for the first time that at least one isoform of FPC is localized to the centrosome and mitotic spindle of dividing cells in multiple cell lines, including MDCK, mIMCD3, LLC-PK1, HEK293, RCTEC and HFCT cells. Using short-hairpin-mediated RNA interference, we show that the inhibition of FPC function in MDCK and mIMCD3 cells leads to centrosome amplification, chromosome lagging and multipolar spindle formation. Consistent with our in vitro findings, we also observed centrosome amplification in the kidneys from human ARPKD patients. These findings demonstrate a novel function of FPC in centrosome duplication and mitotic spindle assembly during cell division. We propose that mitotic defects due to FPC dysfunction contribute to cystogenesis in ARPKD.

Polycystic kidney disease protein fibrocystin localizes to the mitotic spindle and regulates spindle bipolarity

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