Large deletion of Wdr19 in developing renal tubules disrupts primary ciliogenesis leading to polycystic kidney disease in mice

Autosomal dominant polycystic kidney disease (ADPKD) is a genetic disorder in which renal tubules become enormously enlarged due to fluid accumulation. Na(+) -K(+) -ATPase was compared in normal and cystic regions of whole kidneys and in confluent primary cultures of microdissected renal tubule and cyst-lining epithelia. Immunostaining with antibodies directed against the Na(+) -K(+) -ATPase catalytic alpha-subunit was confined to apical, luminal plasma membranes of ADPKD epithelia, which was a complete reversal of the normal renal tubule polarized location in basolateral membranes. Mislocated Na(+) -K(+) -ATPase was shown to be functionally active, because identical intense apical staining was observed by use of a cytochemical assay. In addition, biochemical assays showed a significant increase in these ouabain-inhibitable Na(+) -K(+) -ATPase specific activity levels in ADPKD kidneys compared with age-matched normal kidneys. Specific binding of [3H] ouabain was not only increased but also confined to the apical membrane vesicles prepared from cystic regions of ADPKD kidneys compared with normal age-matched controls, in which binding was confined to basolateral membrane vesicles. Although steady-state levels of Na(+) -K(+) -ATPase alpha- and beta-subunit in mRNAs were increased somewhat in ADPKD kidneys, this alone was not sufficient to account for the observed activation. Confluent ADPKD epithelia grown on dual-chamber, permeable membrane supports also showed reversed polarity of 22NaCl vectorial transport, because this was from basal to apical media compartments. Because this transport could also be blocked by ouabain, this suggested apical Na(+) -K(+) -ATPase was responsible and implicated altered polarity of Na(+) -K(+) -ATPase and resultant Na+ secretion as a mechanism for cyst formation in ADPKD. Because no reversal of polarity of other basolateral or apical membrane proteins was detected, an intracellular sorting defect specific for Na(+) -K(+) -ATPase is proposed.

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Molecular genetics of renal ciliopathies

Biochemical Society Transactions ◽

10.1042/bst20200791 ◽

2021 ◽

Author(s):

Miguel Barroso-Gil ◽

Eric Olinger ◽

John A. Sayer

Keyword(s):

Kidney Disease ◽

Polycystic Kidney Disease ◽

Primary Cilia ◽

Cystic Kidney Disease ◽

Cystic Kidney ◽

Renal Tubules ◽

Polycystic Kidney ◽

Inherited Disorders ◽

Disease Phenotypes ◽

Renal Histology

Renal ciliopathies are a heterogenous group of inherited disorders leading to an array of phenotypes that include cystic kidney disease and renal interstitial fibrosis leading to progressive chronic kidney disease and end-stage kidney disease. The renal tubules are lined with epithelial cells that possess primary cilia that project into the lumen and act as sensory and signalling organelles. Mutations in genes encoding ciliary proteins involved in the structure and function of primary cilia cause ciliopathy syndromes and affect many organ systems including the kidney. Recognised disease phenotypes associated with primary ciliopathies that have a strong renal component include autosomal dominant and recessive polycystic kidney disease and their various mimics, including atypical polycystic kidney disease and nephronophthisis. The molecular investigation of inherited renal ciliopathies often allows a precise diagnosis to be reached where renal histology and other investigations have been unhelpful and can help in determining kidney prognosis. With increasing molecular insights, it is now apparent that renal ciliopathies form a continuum of clinical phenotypes with disease entities that have been classically described as dominant or recessive at both extremes of the spectrum. Gene-dosage effects, hypomorphic alleles, modifier genes and digenic inheritance further contribute to the genetic complexity of these disorders. This review will focus on recent molecular genetic advances in the renal ciliopathy field with a focus on cystic kidney disease phenotypes and the genotypes that lead to them. We discuss recent novel insights into underlying disease mechanisms of renal ciliopathies that might be amenable to therapeutic intervention.

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Pkd1-targeted mutation reveals a role for the Wolffian duct in autosomal dominant polycystic kidney disease

Journal of Developmental Origins of Health and Disease ◽

10.1017/s2040174419000436 ◽

2019 ◽

Vol 11 (1) ◽

pp. 78-85 ◽

Cited By ~ 1

Author(s):

J. B. Tee ◽

A. V. Dnyanmote ◽

M. K. Lorenzo ◽

O. R. Lee ◽

S. Grisaru ◽

...

Keyword(s):

Kidney Disease ◽

Polycystic Kidney Disease ◽

High Throughput Sequencing ◽

Autosomal Dominant ◽

Cyst Formation ◽

Wolffian Duct ◽

Renal Tubules ◽

Polycystic Kidney ◽

Cystic Kidneys ◽

Autosomal Dominant Polycystic Kidney

AbstractSeveral life-threatening diseases of the kidney have their origins in mutational events that occur during embryonic development. In this study, we investigate the role of the Wolffian duct (WD), the earliest embryonic epithelial progenitor of renal tubules, in the etiology of autosomal dominant polycystic kidney disease (ADPKD). ADPKD is associated with a germline mutation of one of the two Pkd1 alleles. For the disease to occur, a second event that disrupts the expression of the other inherited Pkd1 allele must occur. We postulated that this secondary event can occur in the pronephric WD. Using Cre-Lox recombination, mice with WD-specific deletion of one or both Pkd1 alleles were generated. Homozygous Pkd1-targeted deletion in WD-derived tissues resulted in mice with large cystic kidneys and serologic evidence of renal failure. In contrast, heterozygous deletion of Pkd1 in the WD led to kidneys that were phenotypically indistinguishable from control in the early postnatal period. High-throughput sequencing, however, revealed underlying gene and microRNA (miRNA) changes in these heterozygous mutant kidneys that suggest a strong predisposition toward developing ADPKD. Bioinformatic analysis of this data demonstrated an upregulation of several miRNAs that have been previously associated with PKD; pathway analysis further demonstrated that the differentially expressed genes in the heterozygous mutant kidneys were overrepresented in signaling pathways associated with maintenance and function of the renal tubular epithelium. These results suggest that the WD may be an early epithelial target for the genetic or molecular signals that can lead to cyst formation in ADPKD.

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The cell biology of polycystic kidney disease

The Journal of Cell Biology ◽

10.1083/jcb.201006173 ◽

2010 ◽

Vol 191 (4) ◽

pp. 701-710 ◽

Cited By ~ 162

Author(s):

Hannah C. Chapin ◽

Michael J. Caplan

Keyword(s):

Kidney Disease ◽

Polycystic Kidney Disease ◽

Cell Biology ◽

Fluid Transport ◽

Genetic Disorder ◽

Growth Control ◽

Renal Tubules ◽

Polycystic Kidney ◽

Renal Epithelial Cell ◽

Autosomal Dominant Polycystic Kidney

Polycystic kidney disease is a common genetic disorder in which fluid-filled cysts displace normal renal tubules. Here we focus on autosomal dominant polycystic kidney disease, which is attributable to mutations in the PKD1 and PKD2 genes and which is characterized by perturbations of renal epithelial cell growth control, fluid transport, and morphogenesis. The mechanisms that connect the underlying genetic defects to disease pathogenesis are poorly understood, but their exploration is shedding new light on interesting cell biological processes and suggesting novel therapeutic targets.

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KIM-1 and Kidney Disease Progression in Autosomal Dominant Polycystic Kidney Disease: HALT-PKD Results

American Journal of Nephrology ◽

10.1159/000508051 ◽

2020 ◽

Vol 51 (6) ◽

pp. 473-479

Author(s):

Benjamin R. Griffin ◽

Zhiying You ◽

Lama Noureddine ◽

Berenice Gitomer ◽

Loni Perrenoud ◽

...

Keyword(s):

Kidney Disease ◽

Disease Progression ◽

Polycystic Kidney Disease ◽

Autosomal Dominant ◽

Mixed Effects ◽

Kidney Volume ◽

Renal Tubules ◽

Polycystic Kidney ◽

Autosomal Dominant Polycystic Kidney ◽

Over Time

Background: Cyst compression of renal tubules plays a role in the progression of autosomal dominant polycystic kidney disease (ADPKD) and may induce expression of kidney injury molecule-1 (KIM-1). Whether urinary KIM-1 indexed for creatinine (uKIM-1/Cr) is a prognostic marker of disease progression in ADPKD is unknown.In this secondary analysis of a prospective cohort study, we sought to determine whether patients with high as opposed to low uKIM-1/CR at baseline had greater rates of eGFR loss and height-adjusted total kidney volume (HtTKV) increase. Methods: Baseline uKIM-1/Cr values were obtained from 754 participants in Halt Progression of Polycystic Kidney Disease (HALT-PKD) studies A (early ADPKD) and B (late ADPKD). The predictor was uKIM-1/Cr, which was dichotomized by a median value of 0.2417 pg/g, and the primary outcomes were measured longitudinally over time. Mixed-effects linear models were used in the analysis to calculate the annual slope of change in eGFR and HtTKV. Results: Patients with high uKIM-1/Cr (above the median) had an annual decline in eGFR that was 0.47 mL/min greater than that in those with low uKIM-1/Cr (p = 0.0015) after adjustment for all considered covariates. This association was seen in study B patients alone (0.45 mL/min; p = 0.009), but not in study A patients alone (0.42 mL/min; p = 0.06). High baseline uKIM-1/Cr was associated with higher HtTKV in the baseline cross-sectional analysis compared to low uKIM-1/Cr (p = 0.02), but there was no difference between the groups in the mixed-effects model annual slopes. Conclusion: Elevated baseline uKIM-1/Cr is associated with a greater decline in eGFR over time. Further research is needed to determine whether uKIM-1/Cr improves risk stratification in patients with ADPKD.

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Cyst Reduction by Melatonin in a Novel Drosophila Model of Polycystic Kidney Disease

Molecules ◽

10.3390/molecules25225477 ◽

2020 ◽

Vol 25 (22) ◽

pp. 5477

Author(s):

Cassandra Millet-Boureima ◽

Roman Rozencwaig ◽

Felix Polyak ◽

Chiara Gamberi

Keyword(s):

Kidney Disease ◽

Polycystic Kidney Disease ◽

Malpighian Tubules ◽

Cystic Degeneration ◽

Renal Tubules ◽

Potential Candidate ◽

Polycystic Kidney ◽

Melatonin Administration ◽

Drosophila Model ◽

Autosomal Dominant Polycystic Kidney

Autosomal dominant polycystic kidney disease (ADPKD) causes progressive cystic degeneration of the renal tubules, the nephrons, eventually severely compromising kidney function. ADPKD is incurable, with half of the patients eventually needing renal replacement. Treatments for ADPKD patients are limited and new effective therapeutics are needed. Melatonin, a central metabolic regulator conserved across all life kingdoms, exhibits oncostatic and oncoprotective activity and no detected toxicity. Here, we used the Bicaudal C (BicC) Drosophila model of polycystic kidney disease to test the cyst-reducing potential of melatonin. Significant cyst reduction was found in the renal (Malpighian) tubules upon melatonin administration and suggest mechanistic sophistication. Similar to vertebrate PKD, the BicC fly PKD model responds to the antiproliferative drugs rapamycin and mimics of the second mitochondria-derived activator of caspases (Smac). Melatonin appears to be a new cyst-reducing molecule with attractive properties as a potential candidate for PKD treatment.

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Cyst Reduction in a Polycystic Kidney Disease Drosophila Model Using Smac Mimics

Biomedicines ◽

10.3390/biomedicines7040082 ◽

2019 ◽

Vol 7 (4) ◽

pp. 82 ◽

Cited By ~ 3

Author(s):

Cassandra Millet-Boureima ◽

Ramesh Chingle ◽

William D. Lubell ◽

Chiara Gamberi

Keyword(s):

Kidney Disease ◽

Polycystic Kidney Disease ◽

Critical Evaluation ◽

Substantial Reduction ◽

Surrounding Tissue ◽

Renal Tubules ◽

Polycystic Kidney ◽

Precise Knowledge ◽

Drosophila Model ◽

Autosomal Dominant Polycystic Kidney

Autosomal dominant polycystic kidney disease (ADPKD) is an inherited malady affecting 12.5 million people worldwide. Therapeutic options to treat PKD are limited, due in part to lack of precise knowledge of underlying pathological mechanisms. Mimics of the second mitochondria-derived activator of caspases (Smac) have exhibited activity as antineoplastic agents and reported recently to ameliorate cysts in a murine ADPKD model, possibly by differentially targeting cystic cells and sparing the surrounding tissue. A first-in-kind Drosophila PKD model has now been employed to probe further the activity of novel Smac mimics. Substantial reduction of cystic defects was observed in the Malpighian (renal) tubules of treated flies, underscoring mechanistic conservation of the cystic pathways and potential for efficient testing of drug prototypes in this PKD model. Moreover, the observed differential rescue of the anterior and posterior tubules overall, and within their physiologically diverse intermediate and terminal regions implied a nuanced response in distinct tubular regions contingent upon the structure of the Smac mimic. Knowledge gained from studying Smac mimics reveals the capacity for the Drosophila model to precisely probe PKD pharmacology highlighting the value for such critical evaluation of factors implicated in renal function and pathology.

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Prediction of Renal Prognosis in Patients with Autosomal Dominant Polycystic Kidney Disease Using PKD1/PKD2 Mutations

Journal of Clinical Medicine ◽

10.3390/jcm9010146 ◽

2020 ◽

Vol 9 (1) ◽

pp. 146 ◽

Cited By ~ 3

Author(s):

Hiroshi Kataoka ◽

Hinata Fukuoka ◽

Shiho Makabe ◽

Rie Yoshida ◽

Atsuko Teraoka ◽

...

Keyword(s):

Kidney Disease ◽

Polycystic Kidney Disease ◽

Autosomal Dominant ◽

Large Deletion ◽

Polycystic Kidney ◽

Nonsense Mutations ◽

Truncating Mutation ◽

Renal Prognosis ◽

Autosomal Dominant Polycystic Kidney ◽

Pkd2 Mutation

Autosomal dominant polycystic kidney disease (ADPKD) patients with PKD1 mutations, particularly those with truncating mutations, show poor prognosis. However, the differences in disease progression with different mutation types are unclear. Here, a comparative study was conducted on the renal prognosis of patients with ADPKD who were categorized based on genotype (PKD1 versus PKD2 mutation), mutation type (truncating mutation: nonsense, frameshift, splicing mutation, and large deletion; non-truncating mutation: substitution and in-frame deletion), and mutation position. A total of 123 patients visiting our hospital were enrolled. Renal prognosis was poor for those with PKD1 splicing, PKD1 frameshift, and PKD2 splicing mutations. Despite the truncating mutation, the renal prognosis was relatively favorable for patients with nonsense mutations. Three out of five patients with PKD2 mutation required renal replacement therapy before 58 years of age. In conclusion, we showed that renal prognosis differs according to mutation types in both PKD1 and PKD2, and that it was favorable for those with nonsense mutations among patients with PKD1 truncating mutations. It was also confirmed that renal prognosis was not always favorable in patients with PKD2 mutations. A detailed assessment of mutation types may be useful for predicting the renal prognosis of patients with ADPKD.

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Polycystic kidney disease: a predominance of giant nephrons

AJP Renal Physiology ◽

10.1152/ajprenal.1983.244.1.f3 ◽

1983 ◽

Vol 244 (1) ◽

pp. F3-F10 ◽

Cited By ~ 4

Author(s):

J. J. Grantham

Keyword(s):

Kidney Disease ◽

Polycystic Kidney Disease ◽

Renal Tubule ◽

Collecting Duct ◽

The United States ◽

Basement Membranes ◽

Renal Tubules ◽

Polycystic Kidney ◽

Distal Loop ◽

Normal Diameter

Polycystic kidney disease is a bilateral disorder that affects approximately 200,000-400,000 persons in the United States. The most common form of the disease is inherited as an autosomal dominant trait (ADPKD). It typically causes renal insufficiency by the fifth or sixth decade of life. The disease is characterized by the progressive enlargement of a portion of renal tubule segments (proximal, distal, loop of Henle, collecting duct). The tubules enlarge from a normal diameter of 40 microns to several centimeters in diameter, causing marked gross and microscopic anatomic distortion. The cause of the cystic change in the tubules is unknown, but current possibilities include obstruction of tubule fluid flow by hyperplastic tubule cells, increased compliance of the tubule basement membranes, and/or increased radial growth of cells in specific portions of the renal tubule. Several studies show that the epithelia of the cysts continue to transport Na+, K+, Cl-, H+, and organic cations and anions in a qualitative fashion similar to that of the tubule segment from which they were derived. ADPKD, then, is a disease in which some gigantic renal tubules, over a period of several decades, impair the function of nonaffected nephrons and thereby lead to renal failure.

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Dichloroacetate treatment accelerates the development of pathology in rodent autosomal recessive polycystic kidney disease

AJP Renal Physiology ◽

10.1152/ajprenal.00009.2014 ◽

2014 ◽

Vol 307 (10) ◽

pp. F1144-F1148 ◽

Cited By ~ 3

Author(s):

Vincent H. Gattone ◽

Robert L. Bacallao

Keyword(s):

Kidney Disease ◽

Liver Function ◽

Polycystic Kidney Disease ◽

Autosomal Recessive ◽

Renal Tubules ◽

Liver Pathology ◽

Sprague Dawley ◽

Polycystic Kidney ◽

Renal Cystic Disease ◽

Increased Sensitivity

Dichloroacetate (DCA) is a toxicant by-product from the chlorination disinfection process for municipal water. The levels would not affect people with normal renal and liver function. However, people with impaired renal or liver function may have an increased susceptibility to DCA toxicity as those are the organs affected by DCA. People (and rodents) with polycystic kidney disease (PKD) are polyuric, drink more fluids, and have both renal and liver pathology. In PKD, renal tubules and biliary epithelial cells proliferate to form cysts, which can eventually cause renal and/or liver dysfunction. Therefore, PKD may be a predisposing condition with an increased sensitivity to DCA toxicity. PCK rats are an orthologous model of human autosomal recessive PKD and were treated with 75 mg/l DCA in their drinking water. Male and female PCK and male Sprague-Dawley rats were treated from 4 to 8 wk of age, after which the severity of the renal and liver pathology induced by DCA were assessed. Only male PCK rats were adversely affected by DCA treatment, with an increase in the severity of renal cystic disease evinced by an increase in cystic enlargement and proteinuria. In conclusion, the chlorination byproduct DCA may adversely affect those with a preexisting renal disease, especially those who are polydipsic, like those with PKD.

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