bims-bicyki 2022-06-26 papers

bims-bicyki

Biomed News

on Bicaudal-C1 and interactors in cystic kidney disease

Issue of 2022–06–26
eightteen papers selected by
Céline Gagnieux, École Polytechnique Fédérale de Lausanne

Changing Health Disparities in Autosomal Dominant Polycystic Kidney Disease (ADPKD).
The Effect of Dietary Intervention on Autosomal-Dominant Polycystic Kidney Disease (ADPKD) Patients on Tolvaptan and Their Quality of Life.
Automatic cyst and kidney segmentation in autosomal dominant polycystic kidney disease: Comparison of U-Net based methods.
Health Disparities in Autosomal Dominant Polycystic Kidney Disease (ADPKD) in the United States.
Correction to: Is autosomal dominant polycystic kidney disease an early sweet disease?
PF-06409577 inhibits renal cyst progression by concurrently inhibiting the mTOR pathway and CFTR channel activity.
Potential Application of Gambogic Acid for Retarding Renal Cyst Progression in Polycystic Kidney Disease.
Parapelvic Cysts: An Imaging Marker of Kidney Disease Potentially Leading to the Diagnosis of Treatable Rare Genetic Disorders? A Narrative Review of the Literature.
Hedgehog Morphogens Act as Growth Factors Critical to Pre- and Postnatal Cardiac Development and Maturation: How Primary Cilia Mediate Their Signal Transduction.
LUZP1: A new player in the actin-microtubule cross-talk.
CPLANE Complex and Ciliopathies.
Proximal-tubule molecular relay from early Protein diaphanous homolog 1 to late Rho-associated protein kinase 1 regulates kidney function in obesity-induced kidney damage.
Abnormal accumulation of OFD1 in endometrial cancer with poor prognosis inhibits ciliogenesis.
A Case Report of Tolvaptan Therapy for ADPKD Patients With COVID-19. The Need for Appropriate Counselling for Temporary Drug Discontinuation.
Special issue: Cilia and ciliopathies.
Proteolytic control in ciliogenesis: Temporal restriction or early initiation?
The Role of Non-Coding RNAs in Kidney Diseases.
Genome sequencing reveals underdiagnosis of primary ciliary dyskinesia in bronchiectasis.

Clin J Am Soc Nephrol. 2022 Jun 20. pii: CJN.05790522. [Epub ahead of print]

Changing Health Disparities in Autosomal Dominant Polycystic Kidney Disease (ADPKD).

Suzanne F Ruff.



Keywords:  ADPKD; autosomal dominant polycystic kidney disease; chronic kidney disease; chronic renal disease; chronic renal failure; cystic kidney; kidney failure; polycystic kidney disease; transplantation

DOI:  https://doi.org/10.2215/CJN.05790522
Cureus. 2022 May;14(5): e25045

The Effect of Dietary Intervention on Autosomal-Dominant Polycystic Kidney Disease (ADPKD) Patients on Tolvaptan and Their Quality of Life.

Ola Tarabzuni.

  Background and objective Autosomal-dominant polycystic kidney disease (ADPKD) is the most common inherited renal disorder; it affects people of all ethnic groups and is found in up to 10% of patients with end-stage renal disease (ESRD). Dietary intervention is important in people with renal disease, and it has been linked to greater estimated glomerular filtration rate (eGFR) preservation. Tolvaptan, an orally-active nonpeptide, selective arginine vasopressin (AVP) V2R antagonist, was recently licensed in numerous countries for the treatment of ADPKD. The aim of this study was to assess the role of dietary intervention in decreasing the osmotic load on the urine volume and its impact on the quality of life (QOL) of patients with ADPKD on tolvaptan. Methods This prospective cohort study was carried out at a Hamilton nephrology genetics clinic. ADPKD patients on well-tolerated doses of tolvaptan for three months were included in the study. Gitelman and Bartter Symptom Health-related QOL questionnaire was used among the study participants. Results Our study consisted of nine adult patients with ADPKD who were on a stable dose of tolvaptan therapy. Patients had laboratory values for urine volume, sodium (Na), and urea. No significant difference was found between pre- and post-diet intervention values in 24-hour urine volume (5.9 vs. 5.49 L/d; p=0.423), urine Na (p=0.174), and 24-hour urine urea (p=0.404). Conclusion Dietary intervention in ADPKD patients on tolvaptan therapy can play a vital role in improving their QOL. Further research including interventional studies and clinical trials with larger sample sizes is needed to gain deeper insight into the subject.

Keywords:  adpkd; autosomal-dominant polycystic kidney disease; dietary; intervention; quality of life; tolvaptan

DOI:  https://doi.org/10.7759/cureus.25045
Comput Biol Med. 2022 Jul;pii: S0010-4825(22)00223-2. [Epub ahead of print]146 105431

Automatic cyst and kidney segmentation in autosomal dominant polycystic kidney disease: Comparison of U-Net based methods.

Maria Rombolotti, Fabio Sangalli, Domenico Cerullo, Andrea Remuzzi, Ettore Lanzarone.

  Autosomal Dominant Polycystic Kidney Disease is a genetic disease that causes uncontrolled growth of fluid-filled cysts in the kidney. Kidney enlargement resulting from the expansion of cysts is continuous and often associated with decreased renal function and kidney failure. Mouse and rat models are necessary to discover new drugs able to halt the progression of the disease. The analysis of the effects of pharmacological interventions in these models is based on renal morphology and quantification of changes in total renal volume and cyst volume. This requires a proper, reproducible and fast segmentation of the kidney images. We propose a set of fully convolutional networks for kidney and cyst segmentation in micro-CT images, based on the U-Net architecture, to compare them and analyze which ones perform better on contrast-enhanced micro-CT images from normal rats and rats with Autosomal Dominant Polycystic Kidney Disease. Networks have been tested on a series images, and the performance has been evaluated in terms of Intersection over Union and Dice coefficients. Results showed that the best performing networks are the U-Net in which a batch normalization layer is applied after each pair of 3 × 3 convolutions, and the U-Net in which convolutional layers are replaced by inception blocks. Results also showed accurate cyst-to-kidney volume ratios obtained from the segmented images, which is one of main metrics of interest. Finally, segmentation performance has been found to be stable as the images in the training set vary. Therefore, the proposed automatic methodology is suitable and immediately applicable to segment cysts and kidney from micro-CT images, and directly provides the cyst-to-kidney volume ratio.

Keywords:  Autosomal dominant polycystic kidney disease; Cyst and kidney segmentation; Cyst-to-kidney volume ratio; Micro-CT Imaging; U-net architecture

DOI:  https://doi.org/10.1016/j.compbiomed.2022.105431
Clin J Am Soc Nephrol. 2022 Jun 20. pii: CJN.00840122. [Epub ahead of print]

Health Disparities in Autosomal Dominant Polycystic Kidney Disease (ADPKD) in the United States.

Rita L McGill, Milda R Saunders, Alexandra L Hayward, Arlene B Chapman.

   BACKGROUND AND OBJECTIVES: Autosomal dominant polycystic kidney disease (ADPKD) occurs at conception and is often diagnosed decades prior to kidney failure. Nephrology care and transplantation access should be independent of race and ethnicity. However, institutional racism and barriers to health care may affect patient outcomes in ADPKD. We sought to ascertain the effect of health disparities on outcomes in ADPKD by examining age at onset of kidney failure and access to preemptive transplantation and transplantation after dialysis initiation.
DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Retrospective cohort analyses of adults with ADPKD in the United States Renal Data System from January 2000 to June 2018 were merged to US Census income data and evaluated by self-reported race and ethnicity. Age at kidney failure was analyzed in a linear model, and transplant rates before and after dialysis initiation were analyzed in logistic and proportional hazards models in Black and Hispanic patients with ADPKD compared with White patients with ADPKD.
RESULTS: A total of 41,485 patients with ADPKD were followed for a median of 25 (interquartile range, 5-54) months. Mean age was 56±12 years; 46% were women, 13% were Black, and 10% were Hispanic. Mean ages at kidney failure were 55±13, 53±12, and 57±12 years for Black patients, Hispanic patients, and White patients, respectively. Odds ratios for preemptive transplant were 0.33 (95% confidence interval, 0.29 to 0.38) for Black patients and 0.50 (95% confidence interval, 0.44 to 0.56) for Hispanic patients compared with White patients. Transplant after dialysis initiation was 0.61 (95% confidence interval, 0.58 to 0.64) for Black patients and 0.78 (95% confidence interval, 0.74 to 0.83) for Hispanic patients.
CONCLUSIONS: Black and Hispanic patients with ADPKD reach kidney failure earlier and are less likely to receive a kidney transplant preemptively and after initiating dialysis compared with White patients with ADPKD.

Keywords:  United States Renal Data System; autosomal dominant polycystic kidney; disparity; epidemiology and outcomes; equity; ethnicity; kidney transplantation; peritoneal dialysis

DOI:  https://doi.org/10.2215/CJN.00840122
Pediatr Nephrol. 2022 Jun 21.

Correction to: Is autosomal dominant polycystic kidney disease an early sweet disease?

Angélique Dachy, Jean-Paul Decuypere, Rudi Vennekens, François Jouret, Djalila Mekahli.

DOI: https://doi.org/10.1007/s00467-022-05624-z
FEBS Open Bio. 2022 Jun 24.

PF-06409577 inhibits renal cyst progression by concurrently inhibiting the mTOR pathway and CFTR channel activity.

Limin Su, Haoxing Yuan, Haoran Zhang, Ruoqi Wang, Kequan Fu, Long Yin, Ying Ren, Hongli Liu, Qian Fang, Junqi Wang, Dong Guo.

  Renal cyst development and expansion in autosomal dominant polycystic kidney disease (ADPKD) involves over-proliferation of cyst-lining epithelial cells and excessive cystic fluid secretion. While metformin effectively inhibits renal cyst growth in mouse models of ADPKD it exhibits low potency, and thus an AMPK activator with higher potency is required. Herein, we adopted a drug repurposing strategy to explore the potential of PF-06409577, an adenosine monophosphate-activated protein kinase (AMPK) activator for diabetic nephropathy, in cellular, ex vivo and in vivo models of ADPKD. Our results demonstrated that PF-06409577 effectively down-regulated mammalian target of rapamycin (mTOR) pathway-mediated proliferation of cyst-lining epithelial cells and reduced cystic fibrosis transmembrane conductance regulator (CFTR)-regulated cystic fluid secretion. Overall, our data suggest that PF-06409577 holds therapeutic potential for ADPKD treatment.

Keywords:  ADPKD; AMPK; CFTR; PF-06409577; kidney disease; mTOR; renal cyst

DOI:  https://doi.org/10.1002/2211-5463.13459
Molecules. 2022 Jun 15. pii: 3837. [Epub ahead of print]27(12):

Potential Application of Gambogic Acid for Retarding Renal Cyst Progression in Polycystic Kidney Disease.

Nutchanard Khunpatee, Kanit Bhukhai, Varanuj Chatsudthipong, Chaowalit Yuajit.

  Abnormal cell proliferation and accumulation of fluid-filled cysts along the nephrons in polycystic kidney disease (PKD) could lead to a decline in renal function and eventual end-stage renal disease (ESRD). Gambogic acid (GA), a xanthone compound extracted from the brownish resin of the Garcinia hanburyi tree, exhibits various pharmacological properties, including anti-inflammation, antioxidant, anti-proliferation, and anti-cancer activity. However, its effect on inhibiting cell proliferation in PKD is still unknown. This study aimed to determine the pharmacological effects and detailed mechanisms of GA in slowing an in vitro cyst growth model of PKD. The results showed that GA (0.25-2.5 μM) significantly retarded MDCK cyst growth and cyst formation in a dose-dependent manner, without cytotoxicity. Using the BrdU cell proliferation assay, it was found that GA (0.5-2.5 μM) suppressed MDCK and Pkd1 mutant cell proliferation. In addition, GA (0.5-2.5 μM) strongly inhibited phosphorylation of ERK1/2 and S6K expression and upregulated the activation of phosphorylation of AMPK, both in MDCK cells and Pkd1 mutant cells. Taken together, these findings suggested that GA could retard MDCK cyst enlargement, at least in part by inhibiting the cell proliferation pathway. GA could be a natural plant-based drug candidate for ADPKD intervention.

Keywords:  AMPK; ERK1/2; MDCK cyst growth; S6K; gambogic acid

DOI:  https://doi.org/10.3390/molecules27123837
J Nephrol. 2022 Jun 24.

Parapelvic Cysts: An Imaging Marker of Kidney Disease Potentially Leading to the Diagnosis of Treatable Rare Genetic Disorders? A Narrative Review of the Literature.

Ivana Capuano, Pasquale Buonanno, Eleonora Riccio, Felice Crocetto, Antonio Pisani.

  Simple renal cysts are a common finding during abdominal imaging assessment. The incidence increases with age and it is higher in male gender. Parapelvic cysts are a subset of simple cysts that arise within the renal parenchyma, adjacent to the renal sinus, characterized by being generally single, larger, and incompletely surrounded by renal parenchyma. Noteworthy, parapelvic cysts are a rare and understudied condition which, although considered clinically insignificant due to the absence of influence on renal function, still have a controversial aetiopathogenesis. On the other hand, urological management and differential diagnosis have been thoroughly investigated. The aim of our review is to provide an overall vision on this rare condition, usually misdiagnosed and underestimated, on the basis of more recent data. An accurate differential diagnosis of parapelvic cysts can lead to the identification of treatable conditions such as Fabry disease, autosomal dominant polycystic kidney disease, polycystic liver disease and tuberous sclerosis complex disease.

Keywords:  ADPKD; Bosniak classification; Fabry disease; Kidney injury; PLD; Parapelvic cyst; Simple renal cyst; TSC

DOI:  https://doi.org/10.1007/s40620-022-01375-0
Cells. 2022 Jun 09. pii: 1879. [Epub ahead of print]11(12):

Hedgehog Morphogens Act as Growth Factors Critical to Pre- and Postnatal Cardiac Development and Maturation: How Primary Cilia Mediate Their Signal Transduction.

Lindsey A Fitzsimons, Victoria L Brewer, Kerry L Tucker.

  Primary cilia are crucial for normal cardiac organogenesis via the formation of cyto-architectural, anatomical, and physiological boundaries in the developing heart and outflow tract. These tiny, plasma membrane-bound organelles function in a sensory-integrative capacity, interpreting both the intra- and extra-cellular environments and directing changes in gene expression responses to promote, prevent, and modify cellular proliferation and differentiation. One distinct feature of this organelle is its involvement in the propagation of a variety of signaling cascades, most notably, the Hedgehog cascade. Three ligands, Sonic, Indian, and Desert hedgehog, function as growth factors that are most commonly dependent on the presence of intact primary cilia, where the Hedgehog receptors Patched-1 and Smoothened localize directly within or at the base of the ciliary axoneme. Hedgehog signaling functions to mediate many cell behaviors that are critical for normal embryonic tissue/organ development. However, inappropriate activation and/or upregulation of Hedgehog signaling in postnatal and adult tissue is known to initiate oncogenesis, as well as the pathogenesis of other diseases. The focus of this review is to provide an overview describing the role of Hedgehog signaling and its dependence upon the primary cilium in the cell types that are most essential for mammalian heart development. We outline the breadth of developmental defects and the consequential pathologies resulting from inappropriate changes to Hedgehog signaling, as it pertains to congenital heart disease and general cardiac pathophysiology.

Keywords:  Indian Hedgehog; Sonic Hedgehog; congenital heart disease; heart development; organogenesis; primary cilia

DOI:  https://doi.org/10.3390/cells11121879
Eur J Cell Biol. 2022 Jun 15. pii: S0171-9335(22)00053-X. [Epub ahead of print]101(3): 151250

LUZP1: A new player in the actin-microtubule cross-talk.

João Gonçalves.

  LUZP1 (leucine zipper protein 1) was first described as being important for embryonic development. Luzp1 null mice present defective neural tube closure and cardiovascular problems, which cause perinatal death. Since then, LUZP1 has also been implicated in the etiology of diseases like the 1p36 and the Townes-Brocks syndromes, and the molecular mechanisms involving this protein started being uncovered. Proteomics studies placed LUZP1 in the interactomes of the centrosome-cilium interface, centriolar satellites, and midbody. Concordantly, LUZP1 is an actin and microtubule-associated protein, which localizes to the centrosome, the basal body of primary cilia, the midbody, actin filaments and cellular junctions. LUZP1, like its interactor EPLIN, is an actin-stabilizing protein and a negative regulator of primary cilia formation. Moreover, through the regulation of actin, LUZP1 has been implicated in the regulation of cell cycle progression, cell migration and epithelial cell apical constriction. This review discusses the latest findings concerning LUZP1 molecular functions and implications in disease development.

Keywords:  Actin; Centrosome; Cilium; LUZP1; Microtubules

DOI:  https://doi.org/10.1016/j.ejcb.2022.151250
Biomolecules. 2022 Jun 17. pii: 847. [Epub ahead of print]12(6):

CPLANE Complex and Ciliopathies.

Jesús Eduardo Martín-Salazar, Diana Valverde.

  Primary cilia are non-motile organelles associated with the cell cycle, which can be found in most vertebrate cell types. Cilia formation occurs through a process called ciliogenesis, which involves several mechanisms including planar cell polarity (PCP) and the Hedgehog (Hh) signaling pathway. Some gene complexes, such as BBSome or CPLANE (ciliogenesis and planar polarity effector), have been linked to ciliogenesis. CPLANE complex is composed of INTU, FUZ and WDPCP, which bind to JBTS17 and RSG1 for cilia formation. Defects in these genes have been linked to a malfunction of intraflagellar transport and defects in the planar cell polarity, as well as defective activation of the Hedgehog signalling pathway. These faults lead to defective cilium formation, resulting in ciliopathies, including orofacial-digital syndrome (OFDS) and Bardet-Biedl syndrome (BBS). Considering the close relationship, between the CPLANE complex and cilium formation, it can be expected that defects in the genes that encode subunits of the CPLANE complex may be related to other ciliopathies.

Keywords:  CPLANE; cilia; ciliopathies

DOI:  https://doi.org/10.3390/biom12060847
Kidney Int. 2022 Jun 15. pii: S0085-2538(22)00451-3. [Epub ahead of print]

Proximal-tubule molecular relay from early Protein diaphanous homolog 1 to late Rho-associated protein kinase 1 regulates kidney function in obesity-induced kidney damage.

Makiko Ida-Naitoh, Hirobumi Tokuyama, Koji Futatsugi, Marie Yasuda, Keika Adachi, Takeshi Kanda, Yoshiyuki Tanabe, Shu Wakino, Hiroshi Itoh.

  The small GTPase protein RhoA has two effectors, ROCK (Rho-associated protein kinase 1) and mDIA1 (Protein diaphanous homolog 1), which cooperate reciprocally. However, temporal regulation of RhoA and its effectors in obesity-induced kidney damage remains unclear. Here, we investigated the role of RhoA activation in the proximal tubules at the early and late stages of obesity-induced kidney damage. In mice, a three week high-fat diet induced proximal tubule hypertrophy and damage without increased albuminuria, and RhoA/mDIA1 activation without ROCK activation. Conversely, a 12- week high-fat diet induced proximal tubule hypertrophy, proximal tubule damage, increased albuminuria, and RhoA/ROCK activation without mDIA1 elevation. Proximal tubule hypertrophy resulting from cell cycle arrest accompanied by downregulation of the multifunctional cyclin-dependent kinase inhibitor p27Kip1 was elicited by RhoA activation. Mice overexpressing proximal tubule-specific and dominant-negative RHOA display amelioration of high-fat diet-induced kidney hypertrophy, cell cycle abnormalities, inflammation, and renal impairment. In human proximal tubules cells, mechanical stretch mimicking hypertrophy activated ROCK, which triggered inflammation. In human kidney samples from normal individuals with a body mass index of about 25, proximal tubule cell size correlated with body mass index, proximal tubule cell damages, and mDIA1 expression. Thus, RhoA activation in proximal tubules is critical for the initiation and progression of obesity-induced kidney damage. Hence, the switch in the downstream RhoA effector in proximal tubule represents a transition from normal to pathogenic kidney adaptation and to body weight gain, leading to obesity-induced kidney damage.

Keywords:  ROCK; RhoA; hypertrophy; mDIA1; obesity; proximal tubules

DOI:  https://doi.org/10.1016/j.kint.2022.05.018
Oncol Lett. 2022 Jul;24(1): 214

Abnormal accumulation of OFD1 in endometrial cancer with poor prognosis inhibits ciliogenesis.

Ryuji Kojima, Esraa Hassan, Fumiko Ozawa, Chisato Yamada-Namikawa, Shino Ogawa, Shoko Mase, Shinobu Goto, Ryutaro Nishikawa, Hiroshi Inagaki, Yoichi Kato, Mayumi Sugiura-Ogasawara.

  The aim of the present study was to examine primary cilia in endometrial tissue during the menstrual cycle and to clarify their morphological changes with different grades of endometrial cancer. Images of fluorescence immunostaining taken by confocal microscopy were used to count the number of primary cilia in normal endometrium and endometrioid carcinoma Grade 1 and Grade 3 specimens. To examine the association between autophagy and ciliogenesis in endometrioid carcinoma, the expression of p62/Sequestosome-1, a selective substrate for autophagy, and oral-facial-digital syndrome 1 protein (OFD1), a protein associated with ciliogenesis, were examined using images of fluorescence immunostaining taken by confocal microscopy. The level of p62 expression was confirmed by western blotting. In proliferative and secretory endometrial stromal cells, the percentage of cells that were ciliated was 7.2 and 32.7% (95% confidence interval=21.61-39.79; P<0.01), and the length of the primary cilia was 1.24 µm and 2.34 µm (0.92-1.26; P<0.01), respectively. In stromal cells of endometrioid carcinoma Grade 1 and Grade 3, the percentage of ciliated cells was 13.5 and 2.9% (7.89-15.05; P<0.001), and the length of the primary cilia was 2.02 and 1.14 µm (0.76-0.99; P<0.001), respectively. In both normal menstrual cycle tissue and endometrial carcinomas, the percentage of primary cilia was lower and their length was shorter in tissues with higher proliferative potential. The expression of OFD1 was significantly higher in Grade 3 compared with Grade 1 as indicated by quantifying the intensity of the fluorescence images (133-12248; P=0.046). To the best of our knowledge, this is the first study concerning the distribution of primary cilia in normal endometrium and endometrial cancer tissues. Overall, fewer ciliated cells in the highly malignant endometrial cancer tissues may be associated not only to the proliferation of cancer cells, but also to the excessive accumulation of OFD1 due to dysfunctional autophagy.

Keywords:  Sequestosome-1/p62; autophagy; endometrial cancer; endometrium; oral-facial-digital syndrome 1; primary cilia

DOI:  https://doi.org/10.3892/ol.2022.13334
In Vivo. 2022 Jul-Aug;36(4):36(4): 1994-1997

A Case Report of Tolvaptan Therapy for ADPKD Patients With COVID-19. The Need for Appropriate Counselling for Temporary Drug Discontinuation.

Irene Capelli, Francesca Iacovella, Laura Ghedini, Valeria Aiello, Angelodaniele Napoletano, Lorenzo Marconi, Pierluigi Viale, Marco Masina, Gaetano LA Manna.

   BACKGROUND: Patients with autosomal dominant polycystic kidney disease (ADPKD) may require specific therapy with vasopressin receptor antagonists to slow the progression of renal disease. Because of its mechanism of action, the most common side effects are polyuria, nocturia, and polydipsia. Elevations of liver enzyme levels can also occur during treatment with Tolvaptan. Temporary drug withdrawal may be indicated if the patient is unable to hydrate adequately or if there are concomitant causes of dehydration, including major infectious events. During the Coronavirus Disease 2019 (COVID-19) pandemic, this should be considered in the management of patients on Tolvaptan therapy.
CASE REPORT: We present the clinical case of a 51-year-old male with severe acute respiratory syndrome Coronavirus-2 (SARS-CoV-2) infection and ADPKD receiving Tolvaptan therapy with particular reference to the medical management of the patient during the infectious event. The patient was instructed to discontinue promptly Tolvaptan as soon as symptoms appeared. He was treated with forced hydration and symptomatic therapy. Nevertheless, a transient elevation of liver enzyme levels was detected. The timely discontinuation of Tolvaptan therapy avoided the risk of potential hepatotoxicity in a condition of known susceptibility.
CONCLUSION: Tolvaptan therapy of patients with ADPKD is safe even during SARS-CoV-2 infection. There is need for appropriate and prompt patient counseling to avoid potentially adverse side effects.

Keywords:  COVID-19; Tolvaptan; acute kidney injury; case report; polycystic kidney disease

DOI:  https://doi.org/10.21873/invivo.12924
J Cell Physiol. 2022 Jun;237(6): 2611-2612

Special issue: Cilia and ciliopathies.

Chengtian Zhao, Sudipto Roy.

DOI: https://doi.org/10.1002/jcp.30816
Bioessays. 2022 Jun 23. e2200087

Proteolytic control in ciliogenesis: Temporal restriction or early initiation?

Gregor Habeck, Jörg Schweiggert.

  Cellular processes are highly dependent on a dynamic proteome that undergoes structural and functional rearrangements to allow swift conversion between different cellular states. By inducing proteasomal degradation of inhibitory or stimulating factors, ubiquitylation is particularly well suited to trigger such transitions. One prominent example is the remodelling of the centrosome upon cell cycle exit, which is required for the formation of primary cilia - antenna-like structures on the surface of most cells that act as integrative hubs for various extracellular signals. Over the last decade, many reports on ubiquitin-related events involved in the regulation of ciliogenesis have emerged. Very often, these processes are considered to be initiated ad hoc, that is, directly before its effect on cilia biogenesis becomes evident. While such a temporal restriction may hold true for the majority of events, there is evidence that some of them are initiated earlier during the cell cycle. Here, we provide an overview of ubiquitin-dependent processes in ciliogenesis and discuss available data that indicate such an early onset of proteolytic regulation within preceding cell cycle stages.

Keywords:  G0; cell cycle; cilia; posttranslational modification; proteasome; proteolysis; ubiquitin

DOI:  https://doi.org/10.1002/bies.202200087
Int J Mol Sci. 2022 Jun 14. pii: 6624. [Epub ahead of print]23(12):

The Role of Non-Coding RNAs in Kidney Diseases.

Laurent Metzinger, Juan Antonio Moreno, Valérie Metzinger-Le Meuth.

Renal diseases include different pathologies, such as acute kidney injury (AKI), chronic kidney disease (CKD), end-stage renal disease (ESRD), diabetic nephropathy (DN), kidney cancer, polycystic kidney disease, etc [...].

DOI: https://doi.org/10.3390/ijms23126624
Eur Respir J. 2022 Jun 21. pii: 2200176. [Epub ahead of print]

Genome sequencing reveals underdiagnosis of primary ciliary dyskinesia in bronchiectasis.

Genomics England Research Consortium

BACKGROUND: Bronchiectasis can result from infectious, genetic, immunological and allergic causes. 60-80% cases are idiopathic, but a well-recognised genetic cause is the motile ciliopathy, primary ciliary dyskinesia (PCD). Diagnosis of PCD has management implications including addressing co-morbidities, implementing genetic and fertility counselling and future access to PCD-specific treatments. Diagnostic testing can be complex, however PCD genetic testing is rapidly moving from research into clinical diagnostics and would confirm the cause of bronchiectasis.
METHODS: This observational study used genetic data from severe bronchiectasis patients recruited to the UK 100,000 Genomes Project and patients referred for gene panel testing within a tertiary respiratory hospital, Patients referred for genetic testing due to clinical suspicion of PCD were excluded from both analyses. Data was accessed from the British Thoracic Society audit, to investigate whether motile ciliopathies are underdiagnosed in people with bronchiectasis in the UK.
RESULTS: Pathogenic or likely pathogenic variants were identified in motile ciliopathy genes in 17/142 (12%) individuals by whole genome sequencing. Similarly in a single centre with access to pathological diagnostic facilities, 5-10% patients received a PCD diagnosis by gene panel, often linked to normal/inconclusive nasal nitric oxide and cilia functional test results. In 4,898 audited patients with bronchiectasis, <2% were tested for PCD and <1% received genetic testing.
CONCLUSIONS: PCD is underdiagnosed as a cause of bronchiectasis. Increased uptake of genetic testing may help to identify bronchiectasis due to motile ciliopathies and ensure appropriate management.

DOI: https://doi.org/10.1183/13993003.00176-2022