bims-bicyki 2023-03-26 papers

bims-bicyki

Biomed News

on Bicaudal-C1 and interactors in cystic kidney disease

Issue of 2023‒03‒26
thirteen papers selected by
Céline Gagnieux
École Polytechnique Fédérale de Lausanne (EPFL)

Middle Meningeal Artery Embolization for Chronic Subdural Hematoma Related to Autosomal Dominant Polycystic Kidney Disease.
Characteristics and distribution of intracranial aneurysms in Autosomal Dominant Polycystic Kidney Disease patients compared to the general population: a meta-analysis.
Generation of human induced pluripotent stem cell line (BCRTi007-A) from urinary cells of a patient with autosomal dominant polycystic kidney disease.
A Low-Cost Sequencing Platform for Rapid Genotyping in ADPKD and its Impact on Clinical Care.
Association of Longitudinal Urinary Metabolic Biomarkers With ADPKD Severity and Response to Metformin in TAME-PKD Clinical Trial Participants.
Identifying the main predictors of urine output in autosomal-dominant polycystic kidney disease (ADPKD) patients taking tolvaptan.
Apelin is altered in subjects with autosomal dominant polycystic kidney disease and preserved kidney function.
TRPV4 functional status in cystic cells regulates cystogenesis in autosomal recessive polycystic kidney disease during variations in dietary potassium.
Low agreement between various eGFR formulae in pediatric and young adult ADPKD patients.
Label-free proteomic comparison reveals ciliary and non-ciliary phenotypes of IFT-A mutants.
Sniffing out Ca2+ signaling in olfactory cilia.
Application and Study of ROCK Inhibitors in Pulmonary Fibrosis: Recent Developments and Future Perspectives.
Unraveling the intricate cargo-BBSome coupling mechanism at the ciliary tip.

Cureus. 2023 Feb;15(2): e34970

Middle Meningeal Artery Embolization for Chronic Subdural Hematoma Related to Autosomal Dominant Polycystic Kidney Disease.

Hayes B Fountain, Bernardo A de Monaco, Jonathan Jagid, Ronald Benveniste, Joacir G Cordeiro.

  Autosomal dominant polycystic kidney disease (ADPKD) is a connective tissue disease with vascular abnormalities involving multiple organs. The prevalence of ADPKD associated with a spontaneous subdural hematoma (SDH) is very low, with less than 10 cases reported in the literature to date. Symptomatic chronic SDH is classically treated with a twist drill, burr holes, or craniotomy. Recently, middle meningeal artery (MMA) embolization has emerged as an ancillary modality. We present the first case in the literature of a bilateral SDH in a young ADPKD patient successfully managed with MMA embolization. Moreover, we discuss the role of different treatment modalities on this subset of patients.

Keywords:  adpkd; autosomal dominant polycystic kidney disease; bilateral subdural hematoma; chronic subdural hematoma; embolization; middle meningeal artery; mma; neurosurgery; sdh

DOI:  https://doi.org/10.7759/cureus.34970
Kidney360. 2023 Mar 24.

Characteristics and distribution of intracranial aneurysms in Autosomal Dominant Polycystic Kidney Disease patients compared to the general population: a meta-analysis.

Julien Haemmerli, Sandrine Morel, Marc Georges, Fadi Haidar, Fouad T Chebib, Akio Morita, Kazuhiko Nozaki, Teiji Tominaga, Anatoliy V Bervitskiy, Jamil Rzaev, Karl Schaller, Philippe Bijlenga.

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic condition associated with intracranial aneurysms (IAs). The associated pathophysiology remains unknown but an association with wall shear stress (WSS) is suspected. Cerebral arterial location is the principal factor influencing IA natural history. This study aims to compare IA location specific distribution between ADPKD- and non-ADPKD-patients.METHODS: The ADPKD-group was composed of data from a systematic review of the literature (2016-2020, N=7), and three cohorts: @neurIST, Novosibirsk and UCAS. The non-ADPKD-group was formed from the @neurIST, UCAS, ISGC and the Finnish cohort from the literature. Patients and IAs characteristics were compared between ADPKD- and non-ADPKD-groups, and a meta-analysis for IA locations was performed.
RESULTS: 1184 IAs from ADPKD-patients were compared to 21040 IAs from non-ADPKD-patients. 78.6% of ADPKD-patients had hypertension versus 39.2% of non-ADPKD-patients. 32.4% of ADPKD-patients were smokers versus 31.5% of non-ADPKD-patients. 30.1% of ADPKD-patients had a positive family history for IA versus 15.8% of the non-ADPKD-patients. ADPKD-patients showed a higher rate of IA multiplicity (33.2% versus 23.1%). IAs from ADPKD-patients showed a significant predominance across the internal carotid (ICA) and middle cerebral (MCA) arteries. Posterior communicating (Pcom) IAs were more frequently found in the non-ADPKD-group. The meta-analysis confirmed a predominance of IAs in the ADPKD-patients across large caliber arteries (OR (95% CI): ICA: 1.90 (1.10-3.29); MCA: 1.18 (1.02-1.36)). Small diameter arteries such as the Pcom were observed more in non-ADPKD-patients (0.21 (0.11-0.88)).
CONCLUSION: This analysis shows that IAs diagnosed in ADPKD-patients are more often localized in large caliber arteries from the anterior circulation in comparison to IAs in non-ADPKD-patients. It shows that primary cilia driven wall shear stress vessel remodeling to be more critical in cerebral anterior circulation large caliber arteries.

DOI: https://doi.org/10.34067/KID.0000000000000092
Stem Cell Res. 2023 Mar 20. pii: S1873-5061(23)00057-0. [Epub ahead of print]69 103071

Generation of human induced pluripotent stem cell line (BCRTi007-A) from urinary cells of a patient with autosomal dominant polycystic kidney disease.

Lilas Batool, Constanze Raab, Christien Madlen Beez, Andreas Kurtz, Maik Gollasch, Bella Rossbach.

Autosomal dominant polycystic kidney disease (ADPKD) is a common genetic disorder of adults, characterized by uncontrolled cysts formation that causes a gradual impairment of kidney function. We generated a human induced pluripotent stem cell (hiPSC) line from the urinary cells of a patient diagnosed with ADPKD using a non-integrating Epi5™ Episomal iPSC reprogramming strategy. Characterization of the cell line was performed regarding their undifferentiated status, differentiation potential, and quality control for karyotypic integrity, identity, and clearance of reprogramming vectors. The newly derived hiPSC line, namely BCRTi007-A, can be used in vitro for disease modeling of ADPKD as well as testing for novel therapeutic approaches.

DOI: https://doi.org/10.1016/j.scr.2023.103071
Kidney Int Rep. 2023 Mar;8(3): 455-466

A Low-Cost Sequencing Platform for Rapid Genotyping in ADPKD and its Impact on Clinical Care.

Christoph Heinrich Lindemann, Andrea Wenzel, Florian Erger, Lea Middelmann, Julika Borde, Eric Hahnen, Denise Krauß, Simon Oehm, Sita Arjune, Polina Todorova, Kathrin Burgmaier, Max Christoph Liebau, Franziska Grundmann, Bodo B Beck, Roman-Ulrich Müller.

  Introduction: Autosomal-dominant polycystic kidney disease (ADPKD) is the most common genetic cause of kidney failure. Because of the heterogeneity in disease progression in ADPKD, parameters predicting future outcome are important. The disease-causing genetic variant is one of these parameters.Methods: A multiplex polymerase chain reaction (PCR)-based panel (MPP) was established for analysis of 6 polycystic kidney disease (PKD) genes (PKD1, PKD2, HNF1B, GANAB, DZIP1L, and PKHD1) in 441 patients with ADPKD. Selected patients were additionally sequenced using Sanger sequencing or a custom enrichment-based gene panel. Results were combined with clinical characteristics to assess the impact of genetic data on clinical decision-making. Variants of unclear significance (VUS) were considered diagnostic based on a classic ADPKD clinical phenotype.
Results: Using the MPP, disease-causing variants were detected in 65.3% of patients. Sanger sequencing and the custom gene panel in 32 patients who were MPP-negative revealed 20 variants missed by MPP, (estimated overall false negative rate 24.6%, false-positive rate 9.4%). Combining clinical and genetic data revealed that knowledge of the genotype could have impacted the treatment decision in 8.2% of patients with a molecular genetic diagnosis. Sequencing only the PKD1 pseudogene homologous region in MPP-negative patients resulted in an acceptable false-negative rate of 3.28%.
Conclusion: The MPP yields rapid genotype information at lower costs and allows for simple extension of the panel for new disease genes. Additional sequencing of the PKD1 pseudogene homologous region is required in negative cases. Access to genotype information even in settings with limited resources is important to allow for optimal patient counseling in ADPKD.

Keywords:  ADPKD; CKD; PKD; Sanger sequencing; next generation sequencing

DOI:  https://doi.org/10.1016/j.ekir.2022.12.025
Kidney Int Rep. 2023 Mar;8(3): 467-477

Association of Longitudinal Urinary Metabolic Biomarkers With ADPKD Severity and Response to Metformin in TAME-PKD Clinical Trial Participants.

Kenneth R Hallows, Kaleab Z Abebe, Hui Li, Biagio Saitta, Andrew D Althouse, Kyongtae T Bae, Christina M Lalama, Dana C Miskulin, Ronald D Perrone, Stephen L Seliger, Terry J Watnick.

  Introduction: Dysregulated cellular metabolism contributes to autosomal dominant polycystic kidney disease (ADPKD) pathogenesis. The Trial of Administration of Metformin in Polycystic Kidney Disease (TAME-PKD) tested the effects of metformin treatment over 2 years in adult ADPKD patients with mild-moderate disease severity. Metformin was found to be safe and tolerable with an insignificant trend toward reduced estimated glomerular filtration rate (eGFR) decline compared to placebo. Here we tested whether targeted urinary metabolic biomarkers measured in TAME-PKD participants correlated with disease progression, severity, and metformin treatment in cross-sectional and longitudinal analyses.Methods: Concentrations of total protein, targeted metabolites (lactate, pyruvate, and succinate), and glycolytic enzymes (pyruvate kinase-M2, lactate dehydrogenase-A, and pyruvate dehydrogenase kinase-1) were measured and normalized by creatinine or osmolality in urine specimens and compared with height-adjusted total kidney volume (htTKV) and eGFR at the different study timepoints.
Results: In cross-sectional analyses utilizing placebo group data, urinary succinate normalized by creatinine negatively correlated with ln (htTKV), whereas protein excretion strongly positively correlated with ln (htTKV), and negatively correlated with eGFR. Significant time-varying negative associations occurred with eGFR and the lactate/pyruvate ratio and with urine protein normalized by osmolality, indicating correlations of these biomarkers with disease progression. In secondary analyses, urinary pyruvate normalized by osmolality was preserved in metformin-treated participants but declined in placebo over the 2-year study period with a significant between-arm difference, suggesting time-dependent urinary pyruvate changes may serve as a discriminator for metformin treatment effects in this study population.
Conclusion: Proteinuria with enhanced glycolytic and reduced oxidative metabolic markers generally correlated with disease severity and risk of progression in the TAME-PKD study population.

Keywords:  ADPKD; biomarkers; eGFR; metformin; proteinuria

DOI:  https://doi.org/10.1016/j.ekir.2022.11.019
Int Urol Nephrol. 2023 Mar 23.

Identifying the main predictors of urine output in autosomal-dominant polycystic kidney disease (ADPKD) patients taking tolvaptan.

Francisco José Borrego Utiel, Ana Isabel Morales García, Aurora Polo Moyano, Francisco Roca Oporto, Enoc Merino García, Rafael Esteban de la Rosa.

  BACKGROUND: Few works have analyzed factors associated with urine output in ADPKD patients taking tolvaptan (TVP).METHODS: We selected 24-h urine samples from ADPKD patients treated with TVP. Urine osmolality/creatinine ratio was used as estimator of urinary osmolar load.
RESULTS: We included 127 urine samples from 61 patients. After TVP, urine output doubled with a parallel reduction in urine solute concentration. However, when expressed as urine solute/creatinine ratios, no significant changes were observed. Daily osmolar load and osmolality/creatinine ratio did not change significantly. Before TVP, urine output was positively correlated with body weight and urine osmolality/creatinine ratio and negatively with eGFR, urine morning osmolality, and 24-h urine-calculated osmolality. After TVP, urine output was positively correlated with body weight, eGFR and negatively with age. There was a poor correlation with urine-calculated osmolality. We constructed a predictor model using mixed-effects modeling and we found that urine output was related to lower age, higher body weight, higher eGFR, and greater doses of TVP. When body weight was removed, urine output was also related to male sex and a higher daily osmolar excretion. Equation of prediction was: Urine output (mL/day) = 2771-52.9 × Age (years) + 58.4 × Weight (kg) + 18.7 × eGFR (mL/min) + 870 (if TVP = 90/30 mg) + 517 (if TVP = 60/30 mg).
CONCLUSION: Patients taking TVP will undergo an increase about twice in urine production from baseline. Greater doses of TVP cause a progressive increase in urine production. GFR, age, and body weight are the main predictors of future urine output in patients taking TVP.

Keywords:  Autosomal polycystic kidney disease; Glomerular filtration rate; Tolvaptan; Urine osmolar load; Urine output

DOI:  https://doi.org/10.1007/s11255-023-03555-8
Nephrol Dial Transplant. 2023 Mar 21. pii: gfad056. [Epub ahead of print]

Apelin is altered in subjects with autosomal dominant polycystic kidney disease and preserved kidney function.

Peter Janssens, Wilfried Cools, Nadia de Mota, Jean-Paul Decuypere, Vicente Torres, Karl Martin Wissing, Rudi Vennekens, Bert Bammens, Catherine Llorens-Cortes, Djalila Mekahli.

DOI: https://doi.org/10.1093/ndt/gfad056
Physiol Rep. 2023 Mar;11(6): e15641

TRPV4 functional status in cystic cells regulates cystogenesis in autosomal recessive polycystic kidney disease during variations in dietary potassium.

Kyrylo Pyrshev, Anna Stavniichuk, Viktor N Tomilin, Naghmeh Hassanzadeh Khayyat, Guohui Ren, Mariya Kordysh, Oleg Zaika, Mykola Mamenko, Oleh Pochynyuk.

  Mechanosensitive TRPV4 channel plays a dominant role in maintaining [Ca2+ ]i homeostasis and flow-sensitive [Ca2+ ]i signaling in the renal tubule. Polycystic kidney disease (PKD) manifests as progressive cyst growth due to cAMP-dependent fluid secretion along with deficient mechanosensitivity and impaired TRPV4 activity. Here, we tested how regulation of renal TRPV4 function by dietary K+ intake modulates the rate of cystogenesis and mechanosensitive [Ca2+ ]i signaling in cystic cells of PCK453 rats, a homologous model of human autosomal recessive PKD (ARPKD). One month treatment with both high KCl (5% K+ ) and KB/C (5% K+ with bicarbonate/citrate) diets significantly increased TRPV4 levels when compared to control (0.9% K+ ). High KCl diet caused an increased TRPV4-dependent Ca2+ influx, and partial restoration of mechanosensitivity in freshly isolated monolayers of cystic cells. Unexpectedly, high KB/C diet induced an opposite effect by reducing TRPV4 activity and worsening [Ca2+ ]i homeostasis. Importantly, high KCl diet decreased cAMP, whereas high KB/C diet further increased cAMP levels in cystic cells (assessed as AQP2 distribution). At the systemic level, high KCl diet fed PCK453 rats had significantly lower kidney-to-bodyweight ratio and reduced cystic area. These beneficial effects were negated by a concomitant administration of an orally active TRPV4 antagonist, GSK2193874, resulting in greater kidney weight, accelerated cystogenesis, and augmented renal injury. High KB/C diet also exacerbated renal manifestations of ARPKD, consistent with deficient TRPV4 activity in cystic cells. Overall, we demonstrate that TRPV4 channel activity negatively regulates cAMP levels in cystic cells thus attenuating (high activity) or accelerating (low activity) ARPKD progression.

Keywords:  PCK453 rats; [Ca2+]i signaling; cAMP; mechanosensitivity; renal injury

DOI:  https://doi.org/10.14814/phy2.15641
Pediatr Nephrol. 2023 Mar 20.

Low agreement between various eGFR formulae in pediatric and young adult ADPKD patients.

Pieter Schellekens, Marcelien Verjans, Peter Janssens, Angélique Dachy, Stéphanie De Rechter, Luc Breysem, Karel Allegaert, Bert Bammens, Rudi Vennekens, Pieter Vermeersch, Hans Pottel, Djalila Mekahli.

  BACKGROUND: Young autosomal dominant polycystic kidney disease (ADPKD) patients are becoming the new target population for the development of new treatment options. Determination of a reliable equation for estimated glomerular filtration rate (eGFR) from early stages is needed with the promising potential interventional therapies.METHODS: Prospective and longitudinal study on a cohort of 68 genotyped ADPKD patients (age range 0-23 years) with long-term follow-up. Commonly used equations for eGFR were compared for their relative performance.
RESULTS: The revised Schwartz formula (CKiD) showed a highly significant decline in eGFR with aging (- 3.31 mL/min/1.73 m2/year, P < 0.0001). The recently updated equation by the Schwartz group (CKiDU25) showed a smaller (- 0.90 mL/min/1.73 m2/year) but significant (P = 0.001) decline in eGFR with aging and also showed a significant sex difference (P < 0.0001), not observed by the other equations. In contrast, the full age spectrum (FAS) equations (FAS-SCr, FAS-CysC, and the combined) showed no age and sex dependency. The prevalence of hyperfiltration is highly dependent on the formula used, and the highest prevalence was observed with the CKiD Equation (35%).
CONCLUSIONS: The most widely used methods to calculate eGFR in ADPKD children (CKiD and CKiDU25 equations) were associated with unexpected age or sex differences. The FAS equations were age- and sex-independent in our cohort. Hence, the switch from the CKiD to CKD-EPI equation at the transition from pediatric to adult care causes implausible jumps in eGFR, which could be misinterpreted. Having reliable methods to calculate eGFR is indispensable for clinical follow-up and clinical trials. A higher resolution version of the Graphical abstract is available as Supplementary information.

Keywords:  ADPKD; Creatinine; Cystatin c; Estimated glomerular filtration rate; Hyperfiltration; Measured glomerular filtration rate

DOI:  https://doi.org/10.1007/s00467-023-05926-w
bioRxiv. 2023 Mar 09. pii: 2023.03.08.531778. [Epub ahead of print]

Label-free proteomic comparison reveals ciliary and non-ciliary phenotypes of IFT-A mutants.

Janelle C Leggere, Jaime V K Hibbard, Ophelia Papoulas, Chanjae Lee, Chad G Pearson, Edward M Marcotte, John B Wallingford.

DIFFRAC is a powerful method for systematically comparing proteome content and organization between samples in a high-throughput manner. By subjecting control and experimental protein extracts to native chromatography and quantifying the contents of each fraction using mass spectrometry, it enables the quantitative detection of alterations to protein complexes and abundances. Here, we applied DIFFRAC to investigate the consequences of genetic loss of Ift122, a subunit of the intraflagellar transport-A (IFT-A) protein complex that plays a vital role in the formation and function of cilia and flagella, on the proteome of Tetrahymena thermophila . A single DIFFRAC experiment was sufficient to detect changes in protein behavior that mirrored known effects of IFT-A loss and revealed new biology. We uncovered several novel IFT-A-regulated proteins, which we validated through live imaging in Xenopus multiciliated cells, shedding new light on both the ciliary and non-ciliary functions of IFT-A. Our findings underscore the robustness of DIFFRAC for revealing proteomic changes in response to genetic or biochemical perturbation.

DOI: https://doi.org/10.1101/2023.03.08.531778
J Gen Physiol. 2023 Apr 03. pii: e202313378. [Epub ahead of print]155(4):

Sniffing out Ca2+ signaling in olfactory cilia.

Ben Short.

JGP study (Takeuchi and Kurahashi. 2023. J. Gen. Physiol.https://doi.org/10.1085/jgp.202213165) reveals that segregation of signals within sensory cilia allows Ca2+ to play opposing roles in olfactory signal transduction.

DOI: https://doi.org/10.1085/jgp.202313378
J Med Chem. 2023 Mar 20.

Application and Study of ROCK Inhibitors in Pulmonary Fibrosis: Recent Developments and Future Perspectives.

Yuting Xie, Lin Yue, Yaojie Shi, Xingping Su, Cailing Gan, Hongyao Liu, Taixiong Xue, Tinghong Ye.

Rho-associated coiled-coil-containing kinases (ROCKs), serine/threonine protein kinases, were initially identified as downstream targets of the small GTP-binding protein Rho. Pulmonary fibrosis (PF) is a lethal disease with limited therapeutic options and a particularly poor prognosis. Interestingly, ROCK activation has been demonstrated in PF patients and in animal PF models, making it a promising target for PF treatment. Many ROCK inhibitors have been discovered, and four of these have been approved for clinical use; however, no ROCK inhibitors are approved for the treatment of PF patients. In this article, we describe ROCK signaling pathways and the structure-activity relationship, potency, selectivity, binding modes, pharmacokinetics (PKs), biological functions, and recently reported inhibitors of ROCKs in the context of PF. We will also focus our attention on the challenges to be addressed when targeting ROCKs and discuss the strategy of ROCK inhibitor use in the treatment of PF.

DOI: https://doi.org/10.1021/acs.jmedchem.2c01753
Proc Natl Acad Sci U S A. 2023 Mar 28. 120(13): e2218819120

Unraveling the intricate cargo-BBSome coupling mechanism at the ciliary tip.

Yan-Xia Liu, Wen-Juan Li, Rui-Kai Zhang, Sheng-Nan Sun, Zhen-Chuan Fan.

  Certain ciliary transmembrane and membrane-tethered signaling proteins migrate from the ciliary tip to base via retrograde intraflagellar transport (IFT), essential for maintaining their ciliary dynamics to enable cells to sense and transduce extracellular stimuli inside the cell. During this process, the BBSome functions as an adaptor between retrograde IFT trains and these signaling protein cargoes. The Arf-like 13 (ARL13) small GTPase resembles ARL6/BBS3 in facilitating these signaling cargoes to couple with the BBSome at the ciliary tip prior to loading onto retrograde IFT trains for transporting towards the ciliary base, while the molecular basis for how this intricate coupling event happens remains elusive. Here, we report that Chlamydomonas ARL13 only in a GTP-bound form (ARL13GTP) anchors to the membrane for diffusing into cilia. Upon entering cilia, ARL13 undergoes GTPase cycle for shuttling between the ciliary membrane (ARL13GTP) and matrix (ARL13GDP). To achieve this goal, the ciliary membrane-anchored BBS3GTP binds the ciliary matrix-residing ARL13GDP to activate the latter as an ARL13 guanine nucleotide exchange factor. At the ciliary tip, ARL13GTP recruits the ciliary matrix-residing and post-remodeled BBSome as an ARL13 effector to anchor to the ciliary membrane. This makes the BBSome spatiotemporally become available for the ciliary membrane-tethered phospholipase D (PLD) to couple with. Afterward, ARL13GTP hydrolyzes GTP for releasing the PLD-laden BBSome to load onto retrograde IFT trains. According to this model, hedgehog signaling defects associated with ARL13b and BBS3 mutations in humans could be satisfactorily explained, providing us a mechanistic understanding behind BBSome-cargo coupling required for proper ciliary signaling.

Keywords:  ARL13; BBS3; BBSome; bardet–biedl syndrome; cilia

DOI:  https://doi.org/10.1073/pnas.2218819120