Basolateral chloride transporters in autosomal dominant polycystic kidney disease

Transepithelial Cl(-) secretion mediated by apical cystic fibrosis transmembrane conductance regulator (CFTR) Cl(-) channels plays a key role in cyst fluid accumulation in autosomal dominant polycystic kidney disease (ADPKD). The molecular identity of the basolateral transporter(s) responsible for Cl(-) entry in ADPKD cells is unknown, although pharmacological studies suggest that a bumetanide-sensitive Na(+)-K(+)-2Cl(-) cotransporter (NKCC/BSC) is involved. We investigated the expression of NKCC1, CFTR and anion exchanger type I (AE1) in ADPKD kidneys and cultured ADPKD cells. Immunoblotting and immunoprecipitation detected NKCC1 at ~170 kDa in ADPKD cells and kidney extracts. Immunostaining located NKCC1 in one-third of ADPKD cysts, with a pattern of basolateral reactivity. Staining of serial sections showed that cysts positive for NKCC1 also stained for CFTR. Additional studies demonstrated that AE1 is expressed in ADPKD kidneys, and is located at the basolateral pole of CFTR-positive ADPKD cysts that do not express NKCC1. RT-PCR and sequence analyses confirmed the selective expression of NKCC1 or AEI in cultured ADPKD cells that also express CFTR. The fact that most CFTR-positive ADPKD cysts also express NKCC1 suggests that transepithelial Cl(-) secretion in ADPKD involves molecular mechanisms similar to secretory epithelia. AE1 might be an alternative basolateral pathway for Cl(-) in a minority of cysts.     

Claudin-8 modulates paracellular permeability to acidic and basic ions in MDCK II cells

Renal net acid excretion requires tubular reabsorption of filtered bicarbonate, followed by secretion of protons and ammonium in the collecting duct, generating steep transtubular gradients for these ions. To prevent passive backleak of these ions, the tight junctions in the collecting duct must be highly impermeable to these ions. We previously generated a Madin-Darby canine kidney (MDCK II) cell line with inducible expression of claudin-8, a tight junction protein expressed in the collecting duct. In these cells, claudin-8 was shown to function as a paracellular barrier to alkali metal and divalent cations. We have now used this model to test the hypothesis that claudin-8 also functions as a paracellular barrier to acidic or basic ions involved in renal acid excretion. We developed a series of precise and unbiased methods, based on a combination of diffusion potential, short-circuit current, and pH stat measurements, to estimate paracellular permeability to protons, ammonium and bicarbonate in MDCK II cells. We found that under control conditions (i.e. in the absence of claudin-8), these cells are highly permeable to the acidic and basic ions tested. Interestingly, proton permeation exhibited an unusually low activation energy similar to that in bulk solution. This suggests that paracellular proton transfer may occur by a Grotthuss mechanism, implying that the paracellular pores are sufficiently wide to accommodate water molecules in a freely mobile state. Induction of claudin-8 expression reduces permeability not only to protons, but also to ammonium and bicarbonate. We conclude that claudin-8 probably functions to limit the passive leak of these three ions via paracellular routes, thereby playing a permissive role in urinary net acid excretion.     

A key claudin extracellular loop domain is critical for epithelial barrier integrity

Intercellular tight junctions (TJs) regulate epithelial barrier properties. Claudins are major structural constituents of TJs and belong to a large family of tetra-spanning membrane proteins that have two predicted extracellular loops (ELs). Given that claudin-1 is widely expressed in epithelia, we further defined the role of its EL domains in determining TJ function. The effects of several claudin-1 EL mimetic peptides on epithelial barrier structure and function were examined. Incubation of model human intestinal epithelial cells with a 27-amino acid peptide corresponding to a portion of the first EL domain (Cldn-1(53-80)) reversibly interfered with epithelial barrier function by inducing the rearrangement of key TJ proteins: occludin, claudin-1, junctional adhesion molecule-A, and zonula occludens-1. Cldn-1(53-80) associated with both claudin-1 and occludin, suggesting both the direct interference with the ability of these proteins to assemble into functional TJs and their close interaction under physiological conditions. These effects were specific for Cldn-1(53-80), because peptides corresponding to other claudin-1 EL domains failed to influence TJ function. Furthermore, the oral administration of Cldn-1(53-80) to rats increased paracellular gastric permeability. Thus, the identification of a critical claudin-1 EL motif, Cldn-1(53-80), capable of regulating TJ structure and function, offers a useful adjunct to treatments that require drug delivery across an epithelial barrier.     

Heterogeneity of claudin expression by alveolar epithelial cells

Claudins are proteins that participate in epithelial barrier function and regulate paracellular permeability. By immunohistochemistry of adult rat lung sections, claudin-3, claudin-4, and claudin-5 were found to be co-expressed by type II alveolar epithelial cells. Claudin-3 and claudin-4 were also co-expressed by some alveolar epithelial cells adjacent to type II cells. In contrast, claudin-5 was expressed throughout the alveolus. Isolated primary rat alveolar epithelial cells in culture also expressed claudin-3, claudin-4, and claudin-5, but showed little claudin-1 and claudin-2 expression. Claudin expression by isolated cells at both the mRNA and protein level varied with time in culture. In particular, claudin-3 and claudin-5 co-localized and were distributed around the alveolar cell periphery, but claudin-4 expression was heterogeneous. We also found that paracellular permeability was increased when cultured alveolar epithelial cells were treated with a fatty acid amide, methanandamide. Methanandamide did not alter cell viability. Claudin-3, claudin-4, claudin-5, occludin, and zona occludens 1 remained localized to cell-cell contact sites at the plasma membrane in methanandamide-treated cells, suggesting that plasma membrane localization of these junction proteins is not sufficient for maintaining barrier function. However, methanandamide-treated cells showed a 12-fold increase in claudin-5 expression and a 2- to 3-fold increase in claudin-3, consistent with the notion that specific changes in claudin expression levels may correlate with changes in alveolar epithelial barrier function.     

Formation of cysts by principal-like MDCK cells depends on the synergy of cAMP- and ATP-mediated fluid secretion

It has been suggested that more than 70% of the renal cysts in patients with autosomal dominant polycystic kidney disease (ADPKD) arise from the collecting duct and that within this segment cysts originate almost exclusively from principal rather than intercalated cells. The mechanisms for this predisposition of principal cells have so far remained elusive. We, therefore, used Madin–Darby canine kidney (MDCK) subclones resembling principal cells and alpha-intercalated cells in a three-dimensional in vitro model to determine differences in cystogenesis and cyst growth, including the response to cyclic adenosine monophosphate (cAMP) elevation and the dependence on ATP signaling. We found that in vitro cysts developed only from principal-like but not from intercalated-like MDCK cell clones. This specificity could be verified in mixed MDCK cultures enriched for principal- or intercalated-like cells. In vitro cyst growth upon elevation of intracellular cAMP was mainly driven by fluid secretion, rather than increased cell proliferation. The cAMP-dependent fluid secretion was found to depend on extracellular adenosine-5'-triphosphate (ATP) and to act synergistically with purinergic signaling, as the use of the ATP scavenger apyrase, as well as the P2 receptor inhibitor suramin, reduced cAMP-driven fluid secretion, while increasing extracellular ATP potentiated cAMP-mediated cyst growth. In conclusion, we provide in vitro evidence for the ability of principal rather than intercalated cells to form cysts, based on a synergism of cAMP and ATP signaling in enhancing apical fluid secretion.     

Heterogeneity in expression and subcellular localization of tight junction proteins, claudin-10 and -15, examined by RT-PCR and immunofluorescence microscopy

Tight junctions regulate paracellular permeability, create the luminal fluid microenvironment of blood vessels and the digestive tract, and also form the protective barrier in the stratified epithelium including the epidermis. Claudins are the integral membrane proteins at tight junctions and form a multigene family composed of at least 24 members, but knowledge of the subcellular localization of each claudin is still fragmentary. We performed RT-PCR for fifteen claudin species to examine the mRNA expression in various mouse tissues, and focused on investigating the subcellular localization of claudin-10 and -15 by immunofluorescence microscopy in various rat tissues. Neither claudin-10 nor -15 was detected in vascular endothelial cells in most tissues, and these claudins were restricted to the vasa recta in the kidney medulla. Both claudins were also detected at apical tight junctions in the epithelium of the jejunum with no intensity gradients along the crypt-to-villus axis. However, both claudins were expressed only in the basal half of the crypt epithelium in the colon, showing obvious gradients along crypt-to-surface axis. Moreover, claudin-10 showed the ectopic subcellular localization where tight junction strands do not exist. Claudin-10 was detected along the entire lateral membranes of acinar cells in addition to the apical tight junctions in exocrine glands, and in the cytoplasm of basal cells in the stratified epithelium including the dorsal skin and cutaneous stomach. These heterogeneous distributions of claudin-10 and -15 in tissues may be related to the differences in paracellular permeability among tissues.     

Expression of claudin-1, -2, -3, -4, -5 and -7 proteins in benign and malignant canine mammary gland epithelial tumours

Claudins are tight junction proteins expressed by epithelial and endothelial cells. The present study has evaluated the expression of claudin-1, -2, -3, -4, -5 and -7 in 115 hyperplastic and neoplastic lesions of the canine mammary gland and compared this expression with that of normal mammary epithelium. The lesions studied included lobular hyperplasia (n=15), simple adenoma (n=20), non-infiltrating carcinoma in situ (n=20) and infiltrating carcinomas of histological grades I, II and III (n=20 of each). There was strong expression of claudin-1, -3, -4, -5 and -7 by epithelia within examples of lobular hyperplasia and simple adenoma, and strong expression of claudin-3 and -4 by non-infiltrating carcinomas and all three grades of infiltrating carcinoma. By contrast, there was reduced expression of claudin-5 and -7 by non-infiltrating and infiltrating carcinomas and the expression of these two molecules was inversely correlated with histological grade. Claudin-1 was expressed focally within carcinoma in situ, but this molecule was not detected in any invasive carcinoma. Claudin-2 was weakly expressed within areas of lobular hyperplasia and by simple adenomas, but was not expressed by any carcinoma cells. These results suggest that loss or reduction of expression of claudin-1, -2, -5 and -7 may lead to cellular disorientation, detachment and invasion in canine mammary neoplasia.     

Morphological and functional features of hepatic cyst epithelium in autosomal dominant polycystic kidney disease

We evaluated the morphological and functional features of hepatic cyst epithelium in adult autosomal dominant polycystic kidney disease (ADPKD). In six ADPKD patients, we investigated the morphology of cyst epithelium apical surface by scanning electron microscopy and the expression of estrogen receptors (ERs), insulin-like growth factor 1 (IGF1), IGF1 receptors (IGF1-R), growth hormone receptor, the proliferation marker proliferating cell nuclear antigen, and pAKT by immunohistochemistry and immunofluorescence. Proliferation of liver cyst-derived epithelial cells was evaluated by both MTS proliferation assay and [(3)H]thymidine incorporation into DNA. The hepatic cyst epithelium displayed heterogeneous features, being normal in small cysts (<1 cm), characterized by rare or shortened cilia in 1- to 3-cm cysts, and exhibiting the absence of both primary cilia and microvilli in large cysts (>3 cm). Cyst epithelium showed marked immunohistochemical expression of ER, growth hormone receptor, IGF1, IGF1-R, proliferating cell nuclear antigen, and pAKT. IGF1 was 10-fold more enriched in the hepatic cyst fluid than in serum. Serum-deprived liver cyst-derived epithelial cells proliferated when exposed to 17beta-estradiol and IGF1 and when exposed to human cyst fluid. ER or IGF1-R antagonists inhibited the proliferative effect of serum readmission, cyst fluid, 17beta-estradiol, and IGF1. Our findings could explain the role of estrogens in accelerating the progression of ADPKD and may suggest a potential benefit of therapeutic strategies based on estrogen antagonism.     

Tight junction proteins contribute to barrier properties in human pleura

The permeability of pleural mesothelium helps to control the volume and composition of the liquid lubricating pleural surfaces. Information on pleural barrier function in health and disease, however, is scarce. Tissue specimens of human pleura were mounted in Ussing chambers for measurement of transmesothelial resistance. Expression of tight junction (TJ) proteins was studied by Western blots and immune fluorescence confocal microscopy. Both visceral and parietal pleura showed barrier properties represented by transmesothelial resistance. Occludin, claudin-1, -3, -5, and -7, were detected in visceral pleura. In parietal pleura, the same TJ proteins were detected, except claudin-7. In tissues from patients with pleural inflammation these tightening claudins were decreased and in visceral pleura claudin-2, a paracellular channel former, became apparent. We report that barrier function in human pleura coincides with expression of claudins known to be key determinants of epithelial barrier properties. In inflamed tissue, claudin expression indicates a reduced barrier function.     

Activation of transient receptor potential vanilloid subtype 1 increases expression and permeability of tight junction in normal and hyposecretory submandibular gland

Tight junction (TJ) is an important structure that regulates material transport through the paracellular pathway across the epithelium, but its significance in salivary physiology and pathogenesis of salivary dysfunctional diseases is not fully understood. We previously demonstrated that a functional transient receptor potential vanilloid subtype 1 (TRPV1) expresses in submandibular gland (SMG). However, association of TRPV1-induced saliva secretion with TJ remains unknown. Here we explored the effect of TRPV1 activation on expression and function of TJ of rabbit SMG in vitro and in vivo. RT-PCR and western blot analysis revealed that capsaicin upregulated expression of zonula occludin-1 (ZO-1), claudin (Cldn)-3, and -11, but not Cldn-1, -2, -4, -5, and -7 in cultured SMG cells. Capsaicin also increased the entering of 4?kDa FITC-dextran into the acinar lumen, induced redistribution of cytoskeleton F-actin under confocal microscope, and these effects were abolished by preincubation of capsazepine, a TRPV1 antagonist, indicating that activation of TRPV1 increases expression and permeability of TJ in SMG. Additionally, in a hyposecretory model induced by rabbit SMG transplantation, the expression of ZO-1, Cldn-3, and -11 was decreased, whereas other TJs remained unaltered. The structure of TJ was impaired and the width of apical TJs was reduced under transmission electron microscope, concomitant with diminished immunofluorescence of F-actin in peri-apicolateral region, indicating impaired TJ expression and decreased paracellular permeability in the transplanted SMG. Moreover, topical capsaicin cream increased secretion, decreased TJ structural injury, reversed TJ expression levels, and protected F-actin morphology from disarrangement in transplanted SMGs. These data provide the first evidence to demonstrate that TJ components, particularly ZO-1, Cldn-3, and -11 have important roles in secretion of SMG under both physiological and pathophysiological conditions. The injury in TJ integrity was involved in the hypofunctional SMGs, and TRPV1 might be a potential target to improve saliva secretion through modulating expression and function of TJs.     

Different changes in the expression of multiple kinds of tight-junction proteins during ischemia-reperfusion injury of the rat ileum

Dysfunction of tight junctions (TJs), located at the most apical part of the intestinal epithelium, is believed to result in various complications in intestinal disease. However, the behaviors of multiple kinds of TJ proteins during ischemia-reperfusion injury are not understood in detail. To determine changes in expression and localization of TJ proteins during intestinal-barrier recovery, we induced intestinal ischemia-reperfusion injury in rats, measured mucosa-to-blood permeability of fluorescein isothiocyanate-dextran-4 kDa, and compared it with spatiotemporal changes of ZO-1, occludin, and claudin-1, -2, -3, -4, and -5 by immunoconfocal microscopy. At 1 hour post-reperfusion, villi were denuded and intestinal-barrier function was lost. From 6 to 24 hours post-reperfusion, villous epithelium was restored by cell migration, and barrier function together with reticular pattern expression of ZO-1, occludin, and claudin-1, -3, and -5, recovered time-dependently. To the contrary, after ischemia-reperfusion injury, the localized expression of claudin-2 and claudin-4 observed in the non-treated control was lost and replaced with broader expression from crypts to villi with increased basolateral claudin-4 expression in epithelial cells. These data demonstrated that recovery of intestinal barrier function is associated with expression of ZO-1, occludin, and claudin-1, -3, and -5, whereas claudin-2 and claudin-4 show unique changes in expression and localization.     

Cysts in angiomyolipoma with epithelial cysts may be consisted of entrapped and dilated renal tubules: report of a case with additional immunohistochemical evidence to the pre-existing literature

Angiomyolipoma with epithelial cysts (AMLEC) is a distinctive variant of angiomyolipoma characterized by grossly apparent epithelial cysts and a cellular, müllerian-like subepithelial stroma. Some authors suspect that the epithelial cysts mainly represent dilated entrapped native renal collecting duct epithelium, while other authors think that they represented true epithelial differentiation of the AML. Recently, it has been reported that obvious immunolabeling of melanocytic markers such as Melan A and HMB45, which are often immunolabeled in classical angiomyolipoma, are present in epithelial cysts in cases of AMLEC. Here, we report the case of a 43-year-old Japanese woman with AMLEC, and attempt to elucidate the significance of melanocytic marker immunolabeling in the cyst’s epithelium. In the present case, Melan A was labeled in the cyst’s epithelium, and was thought to reflect its labeling in renal tubules existing in the renal parenchyma outside the tumor. This finding may indicate that the cyst epithelium is derived from entrapped renal tubules inside the AML. Non-immunolabeling of the estrogen and progesterone receptors in the cyst epithelium may also suggest that the cyst epithelium is not neoplastic, in contrast to their labeling in neoplastic cells existing in cyst wall. Further examination, such as molecular analysis, is needed to determine whether these epithelial cysts is neoplastic or non-neoplastic.     

Matrix metalloproteinase-9-deficient dendritic cells have impaired migration through tracheal epithelial tight junctions

When sampling inhaled antigens, dendritic cells (DC) must penetrate the tight junction (TJ) barrier while maintaining the TJ seal. In matrix metalloproteinase (MMP)-9-deficient mice, in vivo experiments suggest that migration of DC into air spaces is impaired. To examine the underlying mechanisms, we established a well-defined in vitro model using mouse tracheal epithelial cells and mouse bone marrow DC (BMDC). Transmigration was elicited with either macrophage inflammatory protein (MIP)-1alpha or MIP-3beta in a time-dependent manner. Control MMP-9(+/+) BMDC cultured with granulocyte macrophage-colony-stimulating factor for 7 d showed a 30-fold greater transepithelial migration toward MIP-3beta than MIP-1alpha, indicating a more mature DC phenotype. MMP-9(-/-) BMDC as well as MMP-9(+/+) BMDC in the presence of the MMP inhibitor GM6001, although showing a similar preference for MIP-3beta, were markedly impaired in their ability to traverse the epithelium. Expression levels of CCR5 and CCR7, however, were similar in both MMP-9(-/-) and MMP-9(+/+) BMDC. Expression of the integral TJ proteins, occludin and claudin-1, were examined in BMDC before and after transepithelial migration. Interestingly, occludin but not claudin-1 was degraded following transepithelial migration in both MMP-9(-/-) and control BMDC. In addition, there was a > 2-fold increase in claudin-1 expression in MMP-9(-/-) as compared with control BMDC. These observations indicate that occludin and claudin-1 are differentially regulated and suggest that the lack of MMP-9 may affect claudin-1 turnover.     

Immunohistological characterization of intercellular junction proteins in rhesus macaque intestine

Epithelial junctions play an important role in regulating paracellular permeability and intercellular adhesion. It has been reported that changes in the density of epithelial junctions and/or distribution pattern can contribute to various gastrointestinal (GI) disorders. In this study, we investigated the distribution of the tight junction (Claudins. 1, 3, 4, 5, 7, 10, Zonula Occludens (ZO-1), Occludin), adherens junction (E-cadherin), desmosome (Desmoglein 2, Desmocollin 2) and gap junction (Connexin 43) proteins in the jejunum, ileum and colonic epithelium of healthy rhesus macaques (RM) using immunofluorescence labeling. While proteins in these respective junctions were expressed throughout the jejunum, ileum and colon of RM, we observed differential labeling in epithelial cells from these sites. Claudins 1, 3, 4, 7, E-cadherin and Desmoglein 2 were distributed in the respective intercellular junctions with additional labeling in the lateral membrane of epithelial cells in both small and large intestine. However, claudin 5, claudin 10, ZO-1 and occludin showed uniform distribution in the intercellular junctions of crypt and surface epithelial cells of the intestine. Desmocollin 2 localized predominantly in the upper two thirds along the lateral membrane while desmoglein 2 was distributed along the entire lateral membrane of intestinal epithelial cells. In contrast, connexin 43 exhibited punctate lateral labeling in crypt epithelial cells of the small and large intestine. Our results show diverse localization of epithelial intercellular junction proteins along the intestinal tract of RM. These findings may correlate with differences in paracellular permeability and adhesion along the intestinal tract and could correlate with pathologic disease in these regions of the intestine.     

Claudin‐7 Expressed on Lateral Membrane of Rat Epididymal Epithelium does not Form Aberrant Tight Junction Strands

Claudins are integral membrane proteins at tight junctions (TJs) and form TJ strands. In the present study, we found that claudin‐7 was localized along the entire lateral membranes of epididymal epithelium, including the apical junctional region throughout the epididymis, but claudin‐8 was restricted to the apical junctional region. This finding raises the possibility that aberrant TJ strands may be formed on lateral membranes. Thus, we focused on examining whether TJ strands exist on lateral membranes of epididymal epithelium. Freeze‐fracture electron microscopy showed that aberrant TJ strands were observed in only a few principal cells in all segments of the epididymis except for the initial segment, indicating that the occurrence of aberrant strands is very rare. Aberrant TJ strands were smooth and not subdivided into individual particles in the protoplasmic face, and complementary grooves in the extracellular face were almost free of particles. Aberrant TJ strands in the distal caput and corpus epididymis were accompanied by many vesicle‐like structures but those in the proximal caput and cauda epididymis were not. These results suggest that most of claudin‐7 in lateral membranes may exist in a nonpolymerized form and may play some different roles other than the formation of TJ strands, for example, in the formation of a pool of claudin proteins or in the reinforcement of cell adhesion. Anat Rec, 1431‐1438, 2007. © 2007 Wiley‐Liss, Inc.     

Pax2 gene dosage influences cystogenesis in autosomal dominant polycystic kidney disease

Mutations in PKD1 cause dominant polycystic kidney disease (PKD), characterized by large fluid-filled kidney cysts in adult life, but the molecular mechanism of cystogenesis remains obscure. Ostrom et al. [Dev. Biol., 219, 250-258 (2000)] showed that reduced dosage of Pax2 caused increased apoptosis, and ameliorated cystogenesis in Cpk mutant mice with recessive PKD. Pax2 is expressed in condensing metanephrogenic mesenchyme and arborizing ureteric bud, and plays an important role in kidney development. Transient Pax2 expression during fetal kidney mesenchyme-to-epithelial transition, as well as in nascent tubules, is followed by marked down-regulation of Pax2 expression. Here, we show that in humans with PKD, as well as in Pkd1(del34/del34) mutant mice, Pax2 was expressed in cyst epithelial cells, and facilitated cyst growth in Pkd1(del34/del34) mutant mice. In Pkd1(del34/del34) mutant kidneys, the expression of Pax2 persisted in nascent collecting ducts. In contrast, homozygous Pkd1(del34/del34) fetal mice carrying mutant Pax2 exhibited ameliorated cyst growth, although reduced cystogenesis was not associated with increased apoptosis. Pax2 expression was attenuated in nascent collecting ducts and absent from remnant cysts of Pkd1(del34/del34)/Pax2(1Neu/+) mutant mice. To investigate whether the Pkd1 gene product, Polycystin-1, regulates Pax2, MDCK cells were engineered constitutively expressing wild-type Pkd1; Pax2 protein levels and promoter activity were both repressed in MDCK cells over-expressing Pkd1, but not in cells without transgenic Pkd1. These data suggest that polycystin-1-deficient tubular epithelia persistently express Pax2 in ADPKD, and that Pax2 or its pathway may be an appropriate target for the development of novel therapies for ADPKD.     

The liver in autosomal dominant polycystic kidney disease. Implications for pathogenesis

A histomorphometric and clinico-pathologic analysis of 26 autopsy cases of autosomal dominant polycystic kidney disease (ADPKD) showed that (1) the density of biliary microhamartomas (BMHs) and the stage of polycystic liver disease were strongly correlated, and (2) both were positively correlated with the stage of renal dysfunction and age at autopsy. Using multiple linear regression analysis, only the stage of renal dysfunction was significantly predictive of the density of BMHs, but both variables were simultaneously predictive for the stage of polycystic liver disease. On serial sections, 41.4% of cysts were connected to BMHs and 81.0% of BMHs to portal tracts. Bile-like material was found in 10.7% of BMHs. Flat or polypoid hyperplasia of the epithelium was observed in 2.7% of cysts. These results support the long-maintained view that hepatic cysts in ADPKD result from cystic dilatation of BMHs. They indicate, however, that the number of BMHs increases during life. These observations are consistent with the hypothesis that hepatic and renal cysts in ADPKD have similar pathogeneses, that BMHs and hepatic cysts result from hyperplasia of the bile duct epithelium, and that as they grow, the hepatic cysts become disconnected from the biliary ducts from which they are derived.     

Histogenesis of the renal cysts in adult (autosomal dominant) polycystic kidney disease: a histochemical study

We studied the kidneys from ten patients with adult (autosomal dominant) polycystic kidney disease (APKD) stained with lectins specific for different segments of the nephron on 20 cysts from each case (ranging in size from 0.1 to 1.3 cm in nine cases and from 1.5 to 6 cm in one case). The epithelium of all cysts with positive reactivity (Arachis hypogaea and epithelial membrane antigen) was of collecting duct origin. Many cysts remained unstained. Cysts of proximal tubule origin could not be identified using the specific lectin Lotus tetragonolobus. Focal epithelial hyperplasia appeared in the collecting duct cysts. Cysts surrounded by smooth muscle were frequent and considered to be of collecting duct origin. One case had glomerular cysts. We conclude that the cysts of APKD are principally of collecting duct origin.