bims-bicyki 2022-08-07 papers

bims-bicyki

Biomed News

on Bicaudal-C1 and interactors in cystic kidney disease

Issue of 2022–08–07
eight papers selected by
Céline Gagnieux, École Polytechnique Fédérale de Lausanne

Using the Mayo Imaging Classification to predict renal outcomes in Korean autosomal dominant polycystic kidney disease patients.
Decorating Histones in Polycystic Kidney Disease.
Simultaneous Robotic-Assisted Bilateral Native Nephrectomy and Kidney Transplantation for Autosomal Dominant Polycystic Kidney Disease in Recipients With High Body Mass Index: Report of 2 Cases.
Nuclear Condensation of CDYL Links Histone Crotonylation and Cystogenesis in Autosomal Dominant Polycystic Kidney Disease.
Primary cilia regulate adaptive responses to fasting.
Effect of cilia-induced surface velocity on cerebrospinal fluid exchange in the lateral ventricles.
First detection of primary cilia in injured human anterior cruciate ligament: A pilot study with pathophysiological reflections.
HDAC6 inhibition decreases leukemic stem cell expansion driven by Hedgehog hyperactivation by restoring primary ciliogenesis.

Kidney Res Clin Pract. 2022 Jul;41(4): 389-392

Using the Mayo Imaging Classification to predict renal outcomes in Korean autosomal dominant polycystic kidney disease patients.

Yeonsoon Jung.

DOI: https://doi.org/10.23876/j.krcp.22.016
J Am Soc Nephrol. 2022 Aug 02. pii: ASN.2022070750. [Epub ahead of print]

Decorating Histones in Polycystic Kidney Disease.

Harini Ramalingam, Vishal Patel.



Keywords:  ADPKD; crotonylation; epigenetics; gene expression; histones; phase separation

DOI:  https://doi.org/10.1681/ASN.2022070750
Transplant Proc. 2022 Jul 29. pii: S0041-1345(22)00447-X. [Epub ahead of print]

Simultaneous Robotic-Assisted Bilateral Native Nephrectomy and Kidney Transplantation for Autosomal Dominant Polycystic Kidney Disease in Recipients With High Body Mass Index: Report of 2 Cases.

Mario Spaggiari, Jorge Almario, Gabriela Aguiluz, Lucrezia Furian, Stephen Bartlett, Pierpaolo Di Cocco, Ivo G Tzvetanov, Enrico Benedetti, Pier C Giulianotti.

Robotic kidney transplantation is a safe, reproducible, and less morbid technique in high body mass index and end-stage renal disease. Polycystic kidney disease is a relative contraindication to robotic-assisted kidney transplantation because of the mass effect of the native kidneys on the patient's pelvis that prevents ideal exposure. We report the first 2 cases of robotic-assisted simultaneous bilateral nephrectomy and kidney transplantation for patients with obesity and adult polycystic kidney disease. The recipients were 2 males, 50 and 53 years old, with a body mass index of 35.1 41.6 kg/m2 and 41.6 kg/m2, respectively. Both recipients had suitable living donors. The average operating time was 395 minutes and the estimated blood loss was on average 250 mL. The postoperative course was uneventful and the patients were discharged home on days 4 and 5. Performing robotic nephrectomies simultaneously with kidney transplantation can be done safely, allowing patients with obesity and polycystic kidney disease needing bilateral nephrectomy, to take full advantage of minimally invasive kidney transplantation.

DOI: https://doi.org/10.1016/j.transproceed.2022.03.061
J Am Soc Nephrol. 2022 Aug 02. pii: ASN.2021111425. [Epub ahead of print]

Nuclear Condensation of CDYL Links Histone Crotonylation and Cystogenesis in Autosomal Dominant Polycystic Kidney Disease.

Lin Dang, Xinyi Cao, Tianye Zhang, Yongzhan Sun, Shanshan Tian, Tianyu Gong, Hui Xiong, Peipei Cao, Yuhao Li, Shengqiang Yu, Li Yang, Lirong Zhang, Tong Liu, Kai Zhang, Jing Liang, Yupeng Chen.

   BACKGROUND: Emerging evidence indicates that epigenetic modulation of gene expression plays a key role in the progression of autosomal dominant polycystic kidney disease (ADPKD). However, the molecular basis for how the altered epigenome modulates transcriptional responses, and thereby disease progression in ADPKD, remains largely unknown.
METHODS: Kidneys from control and ADPKD mice were examined for the expression of CDYL and histone acylations. CDYL expression and its correlation with disease severity were analyzed in a cohort of patients with ADPKD. Cdyl transgenic mice were crossed with Pkd1 knockout mice to explore CDYL's role in ADPKD progression. Integrated cistromic and transcriptomic analyses were performed to identify direct CDYL target genes. High-sensitivity mass spectrometry analyses were undertaken to characterize CDYL-regulated histone lysine crotonylations (Kcr). Biochemical analysis and zebrafish models were used for investigating CDYL phase separation.
RESULTS: CDYL was downregulated in ADPKD kidneys, accompanied by an increase of histone Kcr. Genetic overexpression of Cdyl reduced histone Kcr and slowed cyst growth. We identified CDYL-regulated cyst-associated genes, whose downregulation depended on CDYL-mediated suppression of histone Kcr. CDYL assembled nuclear condensates through liquid-liquid phase separation in cultured kidney epithelial cells and in normal kidney tissues. The phase-separating capacity of CDYL was required for efficient suppression of locus-specific histone Kcr, of expression of its target genes, and of cyst growth.
CONCLUSIONS: These results elucidate a mechanism by which CDYL nuclear condensation links histone Kcr to transcriptional responses and cystogenesis in ADPKD.

Keywords:  ADPKD; CDYL; histone crotonylation; phase separation

DOI:  https://doi.org/10.1681/ASN.2021111425
Metabolism. 2022 Aug 01. pii: S0026-0495(22)00151-2. [Epub ahead of print] 155273

Primary cilia regulate adaptive responses to fasting.

Dong Joo Yang, Le Trung Tran, Seul Gi Yoon, Je Kyung Seong, Dong Min Shin, Yun-Hee Choi, Ki Woo Kim.

   OBJECTIVE: Neuronal primary cilia are known to be a required organelle for energy balance and leptin action. However, whether primary cilia directly mediate adaptive responses during starvation is yet unknown. Therefore, we investigated the counterregulatory roles of primary cilia, and their related leptin action in energy-depleted condition.
METHOD: We generated leptin receptor (LepR) neuron-specific primary cilia knockout (Ift88 KOLepR) mice. Leptin-mediated electrophysiological properties of the neurons in fasting condition were assessed using patch-clamp technique. Adaptive responses and neuroendocrine reflexes were measured by monitoring counterregulatory hormones.
RESULTS: In fasting state, the leptin-induced neuronal excitability and leptin homeostasis were impaired in Ift88 KOLepR. In addition, the Ift88 KOLepR exhibited aberrant fasting responses including lesser body weight loss, decreased energy expenditure, and lower heat generation compared to wild-type littermates. Furthermore, the primary cilia in LepR neurons are necessary for counterregulatory responses and leptin-mediated neuroendocrine adaptation to starvation.
CONCLUSION: Our results demonstrated that the neuronal primary cilia are crucial neuronal components mediating the adaptive counterregulatory responses to starvation.

Keywords:  Adaptive response; Homeostasis; Leptin; Primary cilia; Starvation

DOI:  https://doi.org/10.1016/j.metabol.2022.155273
J R Soc Interface. 2022 Aug;19(193): 20220321

Effect of cilia-induced surface velocity on cerebrospinal fluid exchange in the lateral ventricles.

Haruki Yoshida, Shunichi Ishida, Taiki Yamamoto, Takayuki Ishikawa, Yuichi Nagata, Kazuhito Takeuchi, Hironori Ueno, Yohsuke Imai.

  Ciliary motility disorders are known to cause hydrocephalus. The instantaneous velocity of cerebrospinal fluid (CSF) flow is dominated by artery pulsation, and it remains unclear why ciliary dysfunction results in hydrocephalus. In this study, we investigated the effects of cilia-induced surface velocity on CSF flow using computational fluid dynamics. A geometric model of the human ventricles was constructed using medical imaging data. The CSF produced by the choroid plexus and cilia-induced surface velocity were given as the velocity boundary conditions at the ventricular walls. We developed healthy and reduced cilia motility models based on experimental data of cilia-induced velocity in healthy wild-type and Dpcd-knockout mice. The results indicate that there is almost no difference in intraventricular pressure between healthy and reduced cilia motility models. Additionally, it was found that newly produced CSF from the choroid plexus did not spread to the anterior and inferior horns of the lateral ventricles in the reduced cilia motility model. These findings suggest that a ciliary motility disorder could delay CSF exchange in the anterior and inferior horns of the lateral ventricles.

Keywords:  cerebrospinal fluid; computational fluid dynamics; hydrocephalus; lattice Boltzmann method

DOI:  https://doi.org/10.1098/rsif.2022.0321
Pathol Res Pract. 2022 Jul 21. pii: S0344-0338(22)00280-1. [Epub ahead of print]237 154036

First detection of primary cilia in injured human anterior cruciate ligament: A pilot study with pathophysiological reflections.

David Grevenstein, Johannes Oppermann, Lina Winter, Friedrich Barsch, Tanja Niedermair, Andreas Mamilos, Peer Eysel, Christoph Brochhausen.

  The anterior cruciate ligament (ACL) plays a significant role in knee stability, protects the joint under multiple loading conditions and shows complex biomechanics. Beside mechanical stability, the ACL seems to play a crucial role in proprioception, and it is well known, that ACL injuries can cause functional deficits due to decreased proprioception. However, the mechanism of proprioception is not completely understood yet. In this context, primary cilia (PC), which play a significant role in the signaling between the intra- and extracellular space, could be of interest. However, until today, primary cilia are not yet described in human ACL. In total, seven human ACL's underwent transmission electron microscopical examination. Three cadaveric ACL's and four freshly injured ACL's were examined. Single cells of each ACL were examined regarding the presence of axonemes or basal bodies, which represent components of a PC. In total, 276 cells of the cadaveric ACL's and 180 cells of the injured ACL's were examined. Basal bodies could be detected in three of the four specimens of the injured ACL's as well as in one of the three cadaveric ACL's, resulting in a mean positivity of 2.54% in the cadaveric group and 2.78% in the injured group. In case of PC-presence, only one PC per cell could be detected. No statistically significant difference regarding the frequency could be detected between both groups. In this pilot-study, we present for the first time an ultrastructural study of human ACLs with respect to the occurrence of PC and any structural and morphological features of these complex and dynamic cell organelles. PCs are present in almost all non-hematopoietic tissues of the human body. However, there are different reports on the number, incidence, orientation, and morphology of these cell organelles in the respective tissues. Compared to other tissues and ligaments of other species, we found a significantly lower rate of PC positive cells. This observation might represent a tissue-specific characteristic of ACL tissue. However, our observations need to be explored in more detail in further studies.

Keywords:  Anterior cruciate ligament; Ligament damage; Mechanotransduction; Primary cilia; Ultrastructure

DOI:  https://doi.org/10.1016/j.prp.2022.154036
Pharmacol Res. 2022 Jul 30. pii: S1043-6618(22)00323-1. [Epub ahead of print] 106378

HDAC6 inhibition decreases leukemic stem cell expansion driven by Hedgehog hyperactivation by restoring primary ciliogenesis.

Alex Pezzotta, Ilaria Gentile, Donatella Genovese, Maria Grazia Totaro, Cristina Battaglia, Anskar Yu-Hung Leung, Monica Fumagalli, Matteo Parma, Gianni Cazzaniga, Grazia Fazio, Myriam Alcalay, Anna Marozzi, Anna Pistocchi.

  Aberrant activation of the Hh pathway promotes cell proliferation and multi-drug resistance (MDR) in several cancers, including Acute Myeloid Leukemia (AML). Notably, only one Hh inhibitor, glasdegib, has been approved for AML treatment, and most patients eventually relapse, highlighing the urgent need ti discover new therapeutic targets. Hh signal is transduced through the membrane of the primary cilium, a structure expressed by non-proliferating mammalian cells, whose stabilization depends on the activity of HDAC6. Here we describe a positive correlation between Hh, HDAC6, and MDR genes in a cohort of adult AML patients, human leukemic cell lines, and a zebrafish model of Hh overexpression. The hyper-activation of Hh or HDAC6 in zebrafish drove the increased proliferation of hematopoietic stem and progenitor cells (HSPCs). Interestingly, this phenotype was rescued by inhibition of HDAC6 but not of Hh. Also, in human leukemic cell lines, a reduction in vitality was obtained through HDAC6, but not Hh inhibition. Our data showed the presence of a cross-talk between Hh and HDAC6 mediated by stabilization of the primary cilium, which we detect for the first time in zebrafish HSPCs. Inhibition of HDAC6 activity alone or in combination therapy with the chemotherapeutic agent cytarabine, efficiently rescued the hematopoietic phenotype. Our results open the possibility to introduce HDAC6 as therapeutic target to reduce proliferation of leukemic blasts in AML patients.

Keywords:  AML; Dymetil sulfoxide D8418 (Sigma); Glasdegib PZ0303 (Sigma); HDAC6; Hedgehog; Roscovitine R7772 (Sigma); TubastatinA hydrochloride SML0044 (Sigma); cyclopamine hydrate C4116 (Sigma); cytarabine PHR1787 (Sigma); primary cilium; zebrafish

DOI:  https://doi.org/10.1016/j.phrs.2022.106378