bims-bicyki 2022-06-05 papers

bims-bicyki

Biomed News

on Bicaudal-C1 and interactors in cystic kidney disease

Issue of 2022‒06‒05
eighteen papers selected by
Céline Gagnieux
École Polytechnique Fédérale de Lausanne (EPFL)

Ttc21b deficiency attenuates autosomal dominant polycystic kidney disease in a kidney tubular- and maturation-dependent manner.
Deciphering cilia and ciliopathies using proteomic approaches.
Pathophysiology of Primary Cilia: Signaling and Proteostasis Regulation.
Pancreatic extracorporeal shock wave lithotripsy for a patient concurrent with autosomal dominant polycystic kidney disease: a case report.
Chondrocyte-specific response to stiffness-mediated primary cilia formation and centriole positioning.
Potassium Channel KCNH1 Activating Variants Cause Altered Functional and Morphological Ciliogenesis.
Safety of High-Dose 3% Sodium Tetradecyl Sulfate for Sclerotherapy of Renal Cysts in Patients with Autosomal Dominant Polycystic Kidney Disease.
[Polycystic kidneys: Genetic testing and correct classification clinically and therapeutically of increasing significance].
Polycystic Liver and Kidney Disease.
Restriction of intraflagellar transport to some microtubule doublets: An opportunity for cilia diversification?
The Joubert-Meckel-Nephronophthisis Spectrum of Ciliopathies.
UPREGULATED ANGIOTENSIN IA RECEPTORS IN THE HYPOTHALAMIC PVN SENSITISE NEUROENDOCRINE VASOPRESSIN RELEASE AND BLOOD PRESSURE IN A RODENT MODEL OF POLYCYSTIC KIDNEY DISEASE.
Activation of Hedgehog signaling by the oncogenic RELA fusion reveals a primary cilia-dependent vulnerability in Supratentorial Ependymoma.
Insulin controls cytoskeleton reorganization and filtration barrier permeability via the PKGIα-Rac1-RhoA crosstalk in cultured rat podocytes.
A cilia-independent function of BBSome mediated by DLK-MAPK signaling in C. elegans photosensation.
Key gene network related to primary ciliary dyskinesia in hippocampus of patients with Alzheimer's disease revealed by weighted gene co-expression network analysis.
Association of Neonatal Hospital Length of Stay with Lung Function in Primary Ciliary Dyskinesia.
Frequency of Acquired Renal Cystic Disease in Patients on Long-Term Hemodialysis and Associated Renal Cell Carcinoma.

Kidney Int. 2022 May 26. pii: S0085-2538(22)00387-8. [Epub ahead of print]

Ttc21b deficiency attenuates autosomal dominant polycystic kidney disease in a kidney tubular- and maturation-dependent manner.

Wei Wang, Luciane M Silva, Henry H Wang, Matthew A Kavanaugh, Tana S Pottorf, Bailey A Allard, Damon T Jacobs, Rouchen Dong, Joseph T Cornelius, Aakriti Chaturvedi, Katherine I Swenson-Fields, Timothy A Fields, Michele T Pritchard, Madhulika Sharma, Chad Slawson, Darren P Wallace, James P Calvet, Pamela V Tran.

  Primary cilia are sensory organelles built and maintained by intraflagellar transport (IFT) multiprotein complexes. Deletion of several IFT-B genes attenuates polycystic kidney disease (PKD) severity in juvenile and adult autosomal dominant polycystic kidney disease (ADPKD) mouse models. However, deletion of an IFT-A adaptor, Tulp3, attenuates PKD severity in adult mice only. These studies indicate that dysfunction of specific cilia components has potential therapeutic value. To broaden our understanding of cilia dysfunction and its therapeutic potential, we investigate the role of global deletion of an IFT-A gene, Ttc21b, in juvenile and adult mouse models of ADPKD. Both juvenile (postnatal day 21) and adult (six months of age) ADPKD mice exhibited kidney cysts, increased kidney weight/body weight ratios, lengthened kidney cilia, inflammation, and increased levels of the nutrient sensor, O-linked β-N-acetylglucosamine (O-GlcNAc). Deletion of Ttc21b in juvenile ADPKD mice reduced cortical collecting duct cystogenesis and kidney weight/body weight ratios, increased proximal tubular and glomerular dilations, but did not reduce cilia length, inflammation, nor O-GlcNAc levels. In contrast, Ttc21b deletion in adult ADPKD mice markedly attenuated kidney cystogenesis and reduced cilia length, inflammation, and O-GlcNAc levels. Thus, unlike IFT-B, the effect of Ttc21b deletion in mouse models of ADPKD is development-specific. Unlike an IFT-A adaptor, deleting Ttc21b in juvenile ADPKD mice is partially ameliorative. Thus, our studies suggest that different microenvironmental factors, found in distinct nephron segments and in developing versus mature stages, modify ciliary homeostasis and ADPKD pathobiology. Further, elevated levels of O-GlcNAc, which regulates cellular metabolism and ciliogenesis, may be a pathological feature of ADPKD.

Keywords:  IFT139; Thm1; ciliopathy; early-onset; late-onset; renal cystic disease

DOI:  https://doi.org/10.1016/j.kint.2022.04.034
FEBS J. 2022 May 28.

Deciphering cilia and ciliopathies using proteomic approaches.

Xiying Chen, Zhouyuanjing Shi, Feng Yang, Tianhua Zhou, Shanshan Xie.

  Cilia are microtubule-based organelles that protrude from the cell surface and play crucial roles in cellular signaling pathways and extracellular fluid movement. Defects in the ciliary structure and functions are implicated in a set of hereditary disorders, including polycystic kidney disease, nephronophthisis, and Bardet-Biedl syndrome, which are collectively termed as ciliopathies. The application of mass spectrometry-based proteomic approaches to explore ciliary components provides important clues for understanding their physiological and pathological roles. In this review, we focus primarily on proteomic studies involving the identification of proteins in motile cilia and primary cilia, proteomes in ciliopathies, and interactomes of ciliopathy proteins. Collectively, the integration of these data sets will be beneficial for the comprehensive understanding of ciliary structures and exploring potential biomarkers and therapeutic targets for ciliopathies.

Keywords:  cilia; ciliopathies; mass spectrometry; proteomics

DOI:  https://doi.org/10.1111/febs.16538
Front Cell Dev Biol. 2022 ;10 833086

Pathophysiology of Primary Cilia: Signaling and Proteostasis Regulation.

Emanuela Senatore, Rosa Iannucci, Francesco Chiuso, Rossella Delle Donne, Laura Rinaldi, Antonio Feliciello.

  Primary cilia are microtubule-based, non-motile sensory organelles present in most types of growth-arrested eukaryotic cells. They are transduction hubs that receive and transmit external signals to the cells in order to control growth, differentiation and development. Mutations of genes involved in the formation, maintenance or disassembly of ciliary structures cause a wide array of developmental genetic disorders, also known as ciliopathies. The primary cilium is formed during G1 in the cell cycle and disassembles at the G2/M transition. Following the completion of the cell division, the cilium reassembles in G1. This cycle is finely regulated at multiple levels. The ubiquitin-proteasome system (UPS) and the autophagy machinery, two main protein degradative systems in cells, play a fundamental role in cilium dynamics. Evidence indicate that UPS, autophagy and signaling pathways may act in synergy to control the ciliary homeostasis. However, the mechanisms involved and the links between these regulatory systems and cilium biogenesis, dynamics and signaling are not well defined yet. Here, we discuss the reciprocal regulation of signaling pathways and proteolytic machineries in the control of the assembly and disassembly of the primary cilium, and the impact of the derangement of these regulatory networks in human ciliopathies.

Keywords:  E3 ligase; PKA; autophagy; cAMP; proteasome; signaling; ubiquitin

DOI:  https://doi.org/10.3389/fcell.2022.833086
J Int Med Res. 2022 May;50(5): 3000605221100748

Pancreatic extracorporeal shock wave lithotripsy for a patient concurrent with autosomal dominant polycystic kidney disease: a case report.

Dan Wang, Jing Xu, Ya-Wei Bi, Chang-Lin Mei, Zhao-Shen Li, Liang-Hao Hu.

  Whether pancreatic extracorporeal shock wave lithotripsy (ESWL) is safe for patients with autosomal dominant polycystic kidney disease (ADPKD) is unclear. A woman in her early 30s was admitted to our hospital because of intermittent upper abdominal pain and recurrent pancreatitis. The imaging results confirmed the diagnosis of pancreatic stones and ADPKD. We performed pancreatic ESWL using a third-generation lithotripter to pulverize the pancreatic stones. A maximum of 5000 shock waves was delivered per therapeutic session. A second session of ESWL was performed the next day. The patient developed no adverse events or complications related to pancreatic ESWL. Three years after treatment, the patient had developed no relapse of pancreatitis or abdominal pain. Shock waves do not lead to complications such as hematuria, cyst rupture, or deterioration of the inner bleeding of renal cysts. Multiple kidney cysts are not a contraindication for pancreatic ESWL.

Keywords:  Extracorporeal shock wave lithotripsy; abdominal pain; autosomal dominant polycystic kidney disease; case report; chronic pancreatitis; pancreatic stone

DOI:  https://doi.org/10.1177/03000605221100748
Am J Physiol Cell Physiol. 2022 Jun 01.

Chondrocyte-specific response to stiffness-mediated primary cilia formation and centriole positioning.

Ivanna Willantarra, Sophia Leung, Yu Suk Choi, Ashika Chhana, Sue R McGlashan.

  Mechanical stress and the stiffness of the extracellular matrix are key drivers of tissue development and homeostasis. Aberrant mechanosensation is associated with a wide range of pathologies, including osteoarthritis. Matrix (or substrate) stiffness plays a major role in cell spreading, adhesion, proliferation and differentiation. However, how specific cells sense substrate stiffness still remains unclude. The primary cilium is an essential cellular organelle that senses and integrates mechanical and chemical signals from the extracellular environment. We hypothesised that the primary cilium dynamically alters its length and position to fine-tune cell mechanosignalling based on substrate stiffness alone. We used a hydrogel system of varying substrate stiffness to examine the role of stiffness on cilia frequency, length and centriole position as well as cell and nuclei area over time. Contrary to other cell types, we show that chondrocyte primary cilia shorten on softer substrates demonstrating tissue-specific mechanosensing which is aligned with the tissue stiffness the cells originate from. We further show that stiffness determines centriole positioning to either the basal or apical membrane during attachment and spreading, with centriole positioned towards the basal membrane on stiffer substrates. These phenomena are mediated by force generation actin-myosin stress fibres in a time-dependent manner. Finally we show on stiff substrates, that primary cilia are involved in tension-mediated cell spreading. We propose that substrate stiffness plays a role in cilia positioning, regulating cellular responses to external forces, and may be a key driver of mechanosignalling-associated diseases.

Keywords:  Mechanobiology; actin; cell area; extracellular matrix; primary cilia

DOI:  https://doi.org/10.1152/ajpcell.00135.2022
Mol Neurobiol. 2022 May 31.

Potassium Channel KCNH1 Activating Variants Cause Altered Functional and Morphological Ciliogenesis.

Giulia Napoli, Noemi Panzironi, Alice Traversa, Caterina Catalanotto, Valentina Pace, Francesco Petrizzelli, Agnese Giovannetti, Sara Lazzari, Carlo Cogoni, Marco Tartaglia, Massimo Carella, Tommaso Mazza, Antonio Pizzuti, Chiara Parisi, Viviana Caputo.

  The primary cilium is a non-motile sensory organelle that extends from the surface of most vertebrate cells and transduces signals regulating proliferation, differentiation, and migration. Primary cilia dysfunctions have been observed in cancer and in a group of heterogeneous disorders called ciliopathies, characterized by renal and liver cysts, skeleton and limb abnormalities, retinal degeneration, intellectual disability, ataxia, and heart disease and, recently, in autism spectrum disorder, schizophrenia, and epilepsy. The potassium voltage-gated channel subfamily H member 1 (KCNH1) gene encodes a member of the EAG (ether-à-go-go) family, which controls potassium flux regulating resting membrane potential in both excitable and non-excitable cells and is involved in intracellular signaling, cell proliferation, and tumorigenesis. KCNH1 missense variants have been associated with syndromic neurodevelopmental disorders, including Zimmermann-Laband syndrome 1 (ZLS1, MIM #135500), Temple-Baraitser syndrome (TMBTS, MIM #611816), and, recently, with milder phenotypes as epilepsy. In this work, we provide evidence that KCNH1 localizes at the base of the cilium in pre-ciliary vesicles and ciliary pocket of human dermal fibroblasts and retinal pigment epithelial (hTERT RPE1) cells and that the pathogenic missense variants (L352V and R330Q; NP_002229.1) perturb cilia morphology, assembly/disassembly, and Sonic Hedgehog signaling, disclosing a multifaceted role of the protein. The study of KCNH1 localization, its functions related to primary cilia, and the alterations introduced by mutations in ciliogenesis, cell cycle coordination, cilium morphology, and cilia signaling pathways could help elucidate the molecular mechanisms underlying neurological phenotypes and neurodevelopmental disorders not considered as classical ciliopathies but for which a significant role of primary cilia is emerging.

Keywords:  Epilepsy; KCNH1; Neurodevelopmental disorder; Potassium channel; Primary cilium; SHH pathway

DOI:  https://doi.org/10.1007/s12035-022-02886-4
J Vasc Interv Radiol. 2022 Jun;pii: S1051-0443(22)00107-5. [Epub ahead of print]33(6): 715-718

Safety of High-Dose 3% Sodium Tetradecyl Sulfate for Sclerotherapy of Renal Cysts in Patients with Autosomal Dominant Polycystic Kidney Disease.

Neeral R Patel, Steffan Frosi Stella, Mark Nasser, Elizabeth Tai, Ralph Hsiao, Ioan-Andrei Iliuta, Arash Jaberi, John R Kachura, York Pei, Eran Shlomovitz.

This study assessed the safety profile of high-volume (>10 mL) 3% sodium tetradecyl sulfate (STS) sclerotherapy for the treatment of renal cysts in patients with autosomal dominant polycystic kidney disease. A total of 211 sclerotherapy treatments were performed in 169 patients over a 5-year period, with a comparison of 2 patient cohorts based on the STS volumes used. The first cohort (n = 112) received a high volume (greater than 10 mL) of STS, and the second cohort (n = 57) received a low volume (less than 10 mL). The minor adverse event rate for the cohorts was 14.5% and 9.6%, respectively (P = .310), with postprocedure pain being the most common event. One major adverse event occurred, for which the patient required hospitalization for infection after low-volume STS treatment. Doses of STS higher than those currently recommended by the Food and Drug Administration for intravascular use allow large renal cysts to be treated safely in the setting of autosomal dominant polycystic kidney disease.

DOI: https://doi.org/10.1016/j.jvir.2022.02.017
Dtsch Med Wochenschr. 2022 Jun;147(11): 710-717

[Polycystic kidneys: Genetic testing and correct classification clinically and therapeutically of increasing significance].

Carsten Bergmann.

Cystic kidney disease is a clinically and genetically diverse group of diseases, with more than 100 genes known to date. One in 500 is affected worldwide, mostly due to a malfunction of cilia. New genes have been identified recently for the most common form autosomal dominant polycystic kidney disease (ADPKD). Every fourth ADPKD patient is lacking a positive family history (mostly due to a de novo mutation); in these cases remaining family members can be relieved. Differentiation of entities just based on clinical and imaging data is often most challenging. However, an accurate classification is significant for the patient and family. Associated comorbidities and cross-organ complications can be detected early and targeted screening and monitoring can be facilitated. Relatives also benefit from an accurate and early diagnosis. Precise genetic counselling with indication of risks is only possible by knowing the concise disease genotype. Genetic diagnostics is becoming increasingly important in this context and in terms of risk stratification and drug-therapeutic options. The understanding of genotype-phenotype correlations has improved significantly in recent years. Wet and dry lab processes as well as the interpretation of genetic data for ADPKD require a high level of expertise. Differential diagnoses with mutations in other genes underlie patients with "ADPKD" or ADPKD-like phenotypes much more frequently than usually assumed. Due to the number and complexity of genes that need to be considered, a tailored NGS (Next Generation Sequencing) approach using a customized, well-balanced multi-gene panel is cost-effective and currently the method of choice. Differences in the quality of laboratories must be taken into account. With this, the genetic etiology and underlying mutation(s) can be found in most cases.

DOI: https://doi.org/10.1055/a-1337-1828
Clin Gastroenterol Hepatol. 2022 May 25. pii: S1542-3565(22)00521-3. [Epub ahead of print]

Polycystic Liver and Kidney Disease.

Kwabena Oware Adu-Gyamfi, Praneeth Kudaravalli, John Erikson L Yap.



Keywords:  Hepatomegaly; Polycystic Kidney Disease; Polycystic Liver

DOI:  https://doi.org/10.1016/j.cgh.2022.05.011
Bioessays. 2022 May 31. e2200031

Restriction of intraflagellar transport to some microtubule doublets: An opportunity for cilia diversification?

Adeline Mallet, Philippe Bastin.

  Cilia are unique eukaryotic organelles and exhibit remarkable conservation across evolution. Nevertheless, very different types of configurations are encountered, raising the question of their evolution. Cilia are constructed by intraflagellar transport (IFT), the movement of large protein complexes or trains that deliver cilia components to the distal tip for assembly. Recent data revealed that IFT trains are restricted to some but not all nine doublet microtubules in the protist Trypanosoma brucei. Here, we propose that restricted positioning of IFT trains could offer potent options for cilia to evolve towards more complex (addition of new structural elements like in spermatozoa) or simpler configuration (loss of some elements like in primary cilia), and therefore be a driver of cilia diversification. We present two hypotheses to explain how IFT trains could be restricted to some doublets, either by a triage process taking place at the basal body level or by the development of molecular differences between ciliary microtubules.

Keywords:  axoneme; cilia; eukaryotic evolution; flagella; intraflagellar transport; kinesin; microtubule

DOI:  https://doi.org/10.1002/bies.202200031
Annu Rev Genomics Hum Genet. 2022 Jun 02.

The Joubert-Meckel-Nephronophthisis Spectrum of Ciliopathies.

Julie C Van De Weghe, Arianna Gomez, Dan Doherty.

The Joubert syndrome (JS), Meckel syndrome (MKS), and nephronophthisis (NPH) ciliopathy spectrum could be the poster child for advances and challenges in Mendelian human genetics over the past half century. Progress in understanding these conditions illustrates many core concepts of human genetics. The JS phenotype alone is caused by pathogenic variants in more than 40 genes; remarkably, all of the associated proteins function in and around the primary cilium. Primary cilia are near-ubiquitous, microtubule-based organelles that play crucial roles in development and homeostasis. Protruding from the cell, these cellular antennae sense diverse signals and mediate Hedgehog and other critical signaling pathways. Ciliary dysfunction causes many human conditions termed ciliopathies, which range from multiple congenital malformations to adult-onset single-organ failure. Research on the genetics of the JS-MKS-NPH spectrum has spurred extensive functional work exploring the broadly important role of primary cilia in health and disease. This functional work promises to illuminate the mechanisms underlying JS-MKS-NPH in humans, identify therapeutic targets across genetic causes, and generate future precision treatments. Expected final online publication date for the Annual Review of Genomics and Human Genetics, Volume 23 is October 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

DOI: https://doi.org/10.1146/annurev-genom-121321-093528
Neuroendocrinology. 2022 Jun 02.

UPREGULATED ANGIOTENSIN IA RECEPTORS IN THE HYPOTHALAMIC PVN SENSITISE NEUROENDOCRINE VASOPRESSIN RELEASE AND BLOOD PRESSURE IN A RODENT MODEL OF POLYCYSTIC KIDNEY DISEASE.

Conor F Underwood, Peter G R Burke, Natasha N Kumar, Ann K Goodchild, Simon McMullan, Jacqueline K Phillips, Cara M Hildreth.

INTRODUCTION: Angiotensin (Ang) II signalling in the hypothalamic paraventricular nucleus (PVN) via angiotensin type-1a receptors (AT1R) regulates vasopressin release and sympathetic nerve activity - two effectors of blood pressure regulation. We determined the cellular expression and function of AT1R in the PVN of a rodent model of polycystic kidney disease (PKD), the Lewis Polycystic Kidney (LPK) rat, to evaluate its contribution to blood pressure regulation and augmented vasopressin release in PKD.METHODS: PVN AT1R gene expression was quantified with fluorescent in-situ hybridisation in LPK and control rats. PVN AT1R function was assessed with pharmacology under urethane anaesthesia in LPK and control rats instrumented to record arterial pressure and sympathetic nerve activity.
RESULTS: AT1R gene expression was upregulated in the PVN, particularly in CRH neurons, of LPK versus control rats. PVN microinjection of Ang II produced larger increases in systolic blood pressure in LPK versus control rats (36±5 vs. 17±2 mmHg; P<0.01). Unexpectedly, Ang II produced regionally heterogeneous sympathoinhibition (renal: -33%; splanchnic: -12%; lumbar no change) in LPK and no change in controls. PVN pre-treatment with losartan, a competitive AT1R antagonist, blocked the Ang II-mediated renal sympathoinhibition and attenuated the pressor response observed in LPK rats. The Ang II pressor effect was also blocked by systemic OPC-21268, a competitive V1A receptor antagonist, but unaffected by hexamethonium, a sympathetic ganglionic blocker.
DISCUSSION/CONCLUSION: Collectively, our data suggest that upregulated AT1R expression in PVN sensitises neuroendocrine release of vasopressin in the LPK, identifying a central mechanism for the elevated vasopressin levels present in PKD.

DOI: https://doi.org/10.1159/000525337
Neuro Oncol. 2022 May 31. pii: noac147. [Epub ahead of print]

Activation of Hedgehog signaling by the oncogenic RELA fusion reveals a primary cilia-dependent vulnerability in Supratentorial Ependymoma.

Taciani de Almeida Magalhães, Gustavo Alencastro Veiga Cruzeiro, Graziella Ribeiro de Sousa, Bernhard Englinger, Luis Fernando Peinado Nagano, Mathew Ancliffe, Keteryne Rodrigues da Silva, Li Jiang, Johannes Gojo, Yulu Cherry Liu, Brooke Carline, Mani Kuchibhotla, Fabiano Pinto Saggioro, Suely Kazue Nagahashi Marie, Sueli Mieko Oba-Shinjo, José Andres Yunes, Rosane Gomes de Paula Queiroz, Carlos Alberto Scrideli, Raelene Endersby, Mariella G Filbin, Kleiton Silva Borges, Adrian Salic, Luiz Gonzaga Tone, Elvis Terci Valera.

  BACKGROUND: Supratentorial RELA fusion (ST-RELA) ependymomas (EPNs) are resistant tumors without an approved chemotherapeutic treatment. Unfortunately, the molecular mechanisms that leads to chemoresistance traits of ST-RELA remains elusive. The aim of this study was to assess RELA fusion-dependent signaling modules, specifically the role of the Hedgehog (Hh) pathway as a novel targetable vulnerability in ST-RELA.METHODS: Gene expression was analyzed in EPN from patient cohorts, by microarray, RNA-seq, qRT-PCR, and scRNA-seq. Inhibitors against Smoothened (SMO) (Sonidegib) and Aurora-kinase A (AURKA) (Alisertib) were evaluated. Protein expression, primary cilia formation, and drug effects were assessed by immunoblot, immunofluorescence and immunohistochemistry.
RESULTS: Hh components were selectively overexpressed in EPNs induced by the RELA fusion. Single-cell analysis showed that the Hh signature was primarily confined to undifferentiated, stem-like cell subpopulations. Sonidegib exhibited potent growth-inhibitory effects on ST-RELA cells, suggesting a key role for active Hh signaling; importantly, the effect of Sonidegib was reversed by primary cilia loss. We thus tested the effect of AURKA inhibition by Alisertib, to induce cilia stabilization/reassembly. Strikingly, Alisertib rescued ciliogenesis and synergized with Sonidegib in killing ST-RELA cells. Using a xenograft model, we show that cilia loss is a mechanism for acquiring resistance to the inhibitory effect of Sonidegib. However, Alisertib fails to rescue cilia and highlights the need for other strategies to promote cilia reassembly, for treating ST-RELA tumors.
CONCLUSION: Our study reveals a crucial role for the Hh pathway in ST-RELA tumor growth, and suggests that rescue of primary cilia represents a vulnerability of the ST-RELA EPNs.

Keywords:  Alisertib; Hedgehog pathway; ST-RELA ependymoma; Sonidegib; primary cilia

DOI:  https://doi.org/10.1093/neuonc/noac147
Biochim Biophys Acta Mol Cell Res. 2022 May 25. pii: S0167-4889(22)00093-3. [Epub ahead of print]1869(9): 119301

Insulin controls cytoskeleton reorganization and filtration barrier permeability via the PKGIα-Rac1-RhoA crosstalk in cultured rat podocytes.

Patrycja Rachubik, Maria Szrejder, Dorota Rogacka, Marlena Typiak, Irena Audzeyenka, Małgorzata Kasztan, David M Pollock, Stefan Angielski, Agnieszka Piwkowska.

  Podocyte foot processes are an important cellular layer of the glomerular barrier that regulates glomerular permeability. Insulin via the protein kinase G type Iα (PKGIα) signaling pathway regulates the balance between contractility and relaxation (permeability) of the podocyte barrier by regulation of the actin cytoskeleton. This mechanism was shown to be disrupted in diabetes. Rho family guanosine-5'-triphosphates (GTPases) are dynamic modulators of the actin cytoskeleton and expressed in cells that form the glomerular filtration barrier. Thus, changes in Rho GTPase activity may affect glomerular permeability to albumin. The present study showed that Rho family GTPases control podocyte migration and permeability. Moreover these processes are regulated by insulin in PKGIα-dependent manner. Modulation of the PKGI-dependent activity of Rac1 and RhoA GTPases with inhibitors or small-interfering RNA impair glomerular permeability to albumin. We also demonstrated this mechanism in obese, insulin-resistant Zucker rats. We propose that PKGIα-Rac1-RhoA crosstalk is necessary in proper organization of the podocyte cytoskeleton and consequently the stabilization of glomerular architecture and regulation of filtration barrier permeability.

Keywords:  Albuminuria; Filtration barrier permeability; Insulin; Podocytes; Protein kinase G type Iα; Small GTPases

DOI:  https://doi.org/10.1016/j.bbamcr.2022.119301
Dev Cell. 2022 May 26. pii: S1534-5807(22)00333-1. [Epub ahead of print]

A cilia-independent function of BBSome mediated by DLK-MAPK signaling in C. elegans photosensation.

Xinxing Zhang, Jinzhi Liu, Tong Pan, Alex Ward, Jianfeng Liu, X Z Shawn Xu.

  Bardet-Biedl syndrome (BBS) is a genetic disorder that affects primary cilia. BBSome, a protein complex composed of eight BBS proteins, regulates the structure and function of cilia, and its malfunction causes BBS in humans. Here, we report a cilia-independent function of BBSome. To identify genes that regulate the C. elegans photoreceptor protein LITE-1 in ciliated ASH photosensory neurons, we performed a genetic screen and isolated bbs mutants. Functional analysis revealed that BBSome regulates LITE-1 protein stability independently of cilia. Through another round of genetic screening, we found that this cilia-independent function of BBSome is mediated by DLK-MAPK signaling, which acts downstream of BBSome to control LITE-1 stability via Rab5-mediated endocytosis. BBSome exerts its function by regulating the expression of DLK. BBSome also regulates the expression of LZK, a mammalian DLK in human cells. These studies identify a cilia-independent function of BBSome and uncover DLK as an evolutionarily conserved BBSome effector.

Keywords:  BBSome; behavior; cilium; light; nematode; phototransduction; sensory; vision

DOI:  https://doi.org/10.1016/j.devcel.2022.05.005
BMC Neurol. 2022 May 30. 22(1): 198

Key gene network related to primary ciliary dyskinesia in hippocampus of patients with Alzheimer's disease revealed by weighted gene co-expression network analysis.

Pengcheng Xia, Jing Chen, Xiaohui Bai, Ming Li, Le Wang, Zhiming Lu.

  BACKGROUND: Alzheimer's disease (AD) is closely related to aging, showing an increasing incidence rate for years. As one of the main brain regions involved in AD, hippocampus has been extensively studied due to its association with many human diseases. However, little is known about its association with primary ciliary dyskinesia (PCD).MATERIAL AND METHODS: The microarray data of hippocampus on AD were retrieved from the Gene Expression Omnibus (GEO) database to construct the co-expression network by weighted gene co-expression network analysis (WGCNA). The gene network modules associated with AD screened with the common genes were further annotated based on Gene Ontology (GO) database and enriched based on the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. The protein-protein interaction (PPI) network was constructed based on STRING database to identify the hub genes in the network.
RESULTS: Genes involved in PCD were identified in the hippocampus of AD patients. Functional analysis revealed that these genes were mainly enriched in ciliary tissue, ciliary assembly, axoneme assembly, ciliary movement, microtubule based process, microtubule based movement, organelle assembly, axoneme dynamin complex, cell projection tissue, and microtubule cytoskeleton tissue. A total of 20 central genes, e.g., DYNLRB2, ZMYND10, DRC1, DNAH5, WDR16, TTC25, and ARMC4 were identified as hub genes related to PCD in hippocampus of AD patients.
CONCLUSION: Our study demonstrated that AD and PCD have common metabolic pathways. These common pathways provide novel evidence for further investigation of the pathophysiological mechanism and the hub genes suggest new therapeutic targets for the diagnosis and treatment of AD and PCD.
SUBJECTS: Bioinformatics, Cell Biology, Molecular Biology, Neurology.

Keywords:  Alzheimer’s disease; Functional enrichment analysis; Primary ciliary dyskinesia; Protein-protein interaction network; WGCNA; hub gene

DOI:  https://doi.org/10.1186/s12883-022-02724-z
Ann Am Thorac Soc. 2022 Jun 03.

Association of Neonatal Hospital Length of Stay with Lung Function in Primary Ciliary Dyskinesia.

Wallace B Wee, Margaret W Leigh, Stephanie D Davis, Margaret Rosenfeld, Kelli M Sullivan, Michael G Sawras, Thomas W Ferkol, Michael R Knowles, Carlos Milla, Scott D Sagel, Maimoona A Zariwala, Eleanor Pullenayegum, Sharon D Dell.

RATIONALE: Primary ciliary dyskinesia(PCD), an inherited lung disease, is characterized by abnormal ciliary function leading to progressive bronchiectasis. There is wide variability in respiratory disease severity at birth and later in life.OBJECTIVE: To evaluate the association between neonatal hospital length of stay(neonatal-LOS) and supplemental oxygen duration(SuppO2) with lung function in pediatric PCD. We hypothesized that longer neonatal-LOS and SuppO2 are associated with worse lung function (i.e., forced expiratory volume in 1-second percent predicted(FEV1pp)).
METHODS: Secondary analysis of the 'Genetic Disorders of Mucociliary Clearance Consortium' prospective longitudinal multi-center cohort study. Participants enrolled, during 2006-2011, were <19 years old with a confirmed PCD diagnosis and followed annually for 5 years. The exposure variables were neonatal-LOS and SuppO2, counted in days since birth. The outcome, FEV1pp, was measured annually by spirometry. The associations of neonatal-LOS and SuppO2 with FEV1pp were evaluated with a linear mixed effects model with repeated measures and random intercepts, adjusted for age and ciliary ultrastructural defects(EM-defect).
RESULTS: Included were 123 participants (male:47%, mean enrollment age:8.3 years (range:0-18)) with 578 visits (median follow-up:5 years). The median neonatal-LOS was 9 days (range:1-90) and median SuppO2 was 5 days (range:0-180). Neonatal-LOS was associated with worse lung function (-0.27 FEV1pp/day (95%CI:-0.53 to -0.01), p=0.04). SuppO2 was not associated with lung function.
CONCLUSIONS: Neonatal-LOS is associated with worse lung function in pediatric PCD, independent of age and EM-defect. Future research on the mechanisms of neonatal respiratory distress and its management may help us understand the variability of lung health outcomes in PCD.

DOI: https://doi.org/10.1513/AnnalsATS.202202-116OC
Cureus. 2022 Apr;14(4): e24547

Frequency of Acquired Renal Cystic Disease in Patients on Long-Term Hemodialysis and Associated Renal Cell Carcinoma.

Furqan Ali, Jibran Bin Aziz, Shahzaib Saleem, Sania Ishtiaq Khan, Saadat Khan, Sanam I Khan.

  Background Acquired cystic renal disease is one of the complications of end-stage renal disease (ESRD) patients on dialysis. We aimed to define the prevalence of acquired cystic renal disease in a dialysis center in a tertiary care setup in Pakistan. Materials and methods We conducted a cross-sectional study of 246 patients with ESRD from October 1, 2017, to March 30, 2018. We collected patient demographic data, comorbidities, duration (years), frequency (sessions/week), length of each dialysis session (hours), ultrasound findings, cystic renal disease occurrence, and associated complications for analysis. Results Our patient population consisted of 115 women (46.7%) and 131 men (53.3%) and had a mean age of 55.9 ± 15.1 years. Thirty-seven patients were on dialysis for one year, 78 (31.7%) for two years, and 131 (53.3%) for three or more years, as its more common with increasing duration. The mean dialysis duration was 2.3 ± 0.7 years. Of 246 patients, 49 (19.9%) had acquired cystic renal disease. Conclusions Given improved health care facilities, an increasing number of patients have a good survival on dialysis and develop long-term complications associated with end-stage renal disease, such as acquired cystic renal disease. Because the acquired renal cystic disease is associated with renal cell carcinoma, physicians should evaluate dialysis patients for renal cell carcinoma, especially after three to five years of dialysis.

Keywords:  acquired cystic renal disease (acrd); chronic renal failure; end stage renal disease (esrd); hemodialysis; renal cell carcinoma (rcc)

DOI:  https://doi.org/10.7759/cureus.24547