bims-bicyki 2020-12-06 papers

bims-bicyki

Biomed News

on Bicaudal-C1 and interactors in cystic kidney disease

Issue of 2020‒12‒06
eight papers selected by
Céline Gagnieux
École Polytechnique Fédérale de Lausanne (EPFL)

The Controversial Role of Fibrosis in Autosomal Dominant Polycystic Kidney Disease.
Autosomal Dominant Polycystic Kidney Disease does not significantly alter major COVID-19 outcomes among veterans.
Novel Potential Application of Chitosan Oligosaccharide for Attenuation of Renal Cyst Growth in the Treatment of Polycystic Kidney Disease.
A non-canonical Hedgehog pathway initiates ciliogenesis and autophagy.
Percutaneous nephrolithotomy under X ray free technique in upper urinary stone patients with autosomal dominant polycystic kidney disease: experience from a large-volume stone management center.
Semi-Mechanistic Pharmacokinetic Model to Guide the Dose Selection of Nimotuzumab in Patients with Autosomal Dominant Polycystic Kidney Disease.
Proline-rich tyrosine kinase 2 mediates transforming growth factor-beta-induced hepatic stellate cell activation and liver fibrosis.
Single-Base Resolution: Increasing the Specificity of the CRISPR-Cas System in Gene Editing.

Int J Mol Sci. 2020 Nov 25. pii: E8936. [Epub ahead of print]21(23):

The Controversial Role of Fibrosis in Autosomal Dominant Polycystic Kidney Disease.

Maria Fragiadaki, Fiona M Macleod, Albert C M Ong.

  Autosomal Dominant Polycystic Kidney Disease (ADPKD) is characterized by the progressive growth of cysts but it is also accompanied by diffuse tissue scarring or fibrosis. A number of recent studies have been published in this area, yet the role of fibrosis in ADPKD remains controversial. Here, we will discuss the stages of fibrosis progression in ADPKD, and how these compare with other common kidney diseases. We will also provide a detailed overview of some key mechanistic pathways to fibrosis in the polycystic kidney. Specifically, the role of the 'chronic hypoxia hypothesis', persistent inflammation, Transforming Growth Factor beta (TGFβ), Janus Kinase/Signal Transducers and Activators of Transcription (JAK/STAT) and microRNAs will be examined. Evidence for and against a pathogenic role of extracellular matrix during ADPKD disease progression will be provided.

Keywords:  ADPKD; EMT; JAK/STAT; PKD1; PKD2; TGFβ; extracellular matrix (ECM); fibrosis; hypoxia; microRNAs

DOI:  https://doi.org/10.3390/ijms21238936
medRxiv. 2020 Nov 29. pii: 2020.11.25.20238675. [Epub ahead of print]

Autosomal Dominant Polycystic Kidney Disease does not significantly alter major COVID-19 outcomes among veterans.

Xiangqin Cui, Julia W Gallini, Christine L Jasien, Michal Mrug.

Chronic kidney disease (CKD), as well as its common causes (e.g., diabetes and obesity), are recognized risk factors for severe COVID-19 illness. To explore whether the most common inherited cause of CKD, autosomal dominant polycystic kidney disease (ADPKD), is also an independent risk factor, we studied data from the VA health system and the VA COVID-19-shared resources (e.g., ICD codes, demographics, pre-existing conditions, pre-testing symptoms, and post-testing outcomes). Among 61 COVID-19-positive ADPKD patients, 21 (34.4%) were hospitalized, 10 (16.4%) were admitted to ICU, 4 (6.6%) required ventilator, and 4 (6.6%) died by August 18, 2020. These rates were comparable to patients with other cystic kidney diseases and cystic liver-only diseases. ADPKD was not a significant risk factor for any of the four outcomes in multivariable logistic regression analyses when compared with other cystic kidney diseases and cystic liver-only diseases. In contrast, diabetes was a significant risk factor for hospitalization [OR 2.30 (1.61, 3.30), p<0.001], ICU admission [OR 2.23 (1.47, 3.42), p<0.001], and ventilator requirement [OR 2.20 (1.27, 3.88), p=0.005]. Black race significantly increased the risk for ventilator requirement [OR 2.00 (1.18, 3.44), p=0.011] and mortality [OR 1.60 (1.02, 2.51), p=0.040]. We also examined the outcome of starting dialysis after COVID-19 confirmation. The main risk factor for starting dialysis was CKD [OR 6.37 (2.43, 16.7)] and Black race [OR 3.47 (1.48, 8.1)]. After controlling for CKD, ADPKD did not significantly increase the risk for newly starting dialysis comparing with other cystic kidney diseases and cystic liver-only diseases. In summary, ADPKD did not significantly alter major COVID-19 outcomes among veterans when compared to other cystic kidney and liver patients.

DOI: https://doi.org/10.1101/2020.11.25.20238675
Molecules. 2020 Nov 27. pii: E5589. [Epub ahead of print]25(23):

Novel Potential Application of Chitosan Oligosaccharide for Attenuation of Renal Cyst Growth in the Treatment of Polycystic Kidney Disease.

Nutthapoom Pathomthongtaweechai, Sunhapas Soodvilai, Rath Pichyangkura, Chatchai Muanprasat.

  Chitosan oligosaccharide (COS), a natural polymer derived from chitosan, exerts several biological activities including anti-inflammation, anti-tumor, anti-metabolic syndrome, and drug delivery enhancer. Since COS is vastly distributed to kidney and eliminated in urine, it may have a potential advantage as the therapeutics of kidney diseases. Polycystic kidney disease (PKD) is a common genetic disorder characterized by multiple fluid-filled cysts, replacing normal renal parenchyma and leading to impaired renal function and end-stage renal disease (ESRD). The effective treatment for PKD still needs to be further elucidated. Interestingly, AMP-activated protein kinase (AMPK) has been proposed as a drug target for PKD. This study aimed to investigate the effect of COS on renal cyst enlargement and its underlying mechanisms. We found that COS at the concentrations of 50 and 100 µg/mL decreased renal cyst growth without cytotoxicity, as measured by MTT assay. Immunoblotting analysis showed that COS at 100 µg/mL activated AMPK, and this effect was abolished by STO-609, a calcium/calmodulin-dependent protein kinase kinase beta (CaMKKβ) inhibitor. Moreover, COS elevated the level of intracellular calcium. These results suggest that COS inhibits cyst progression by activation of AMPK via CaMKKβ. Therefore, COS may hold the potential for pharmaceutical application in PKD.

Keywords:  AMP-activated protein kinase; chitosan oligosaccharide; drug discovery; polycystic kidney disease; renal cyst

DOI:  https://doi.org/10.3390/molecules25235589
J Cell Biol. 2021 Jan 04. pii: e202004179. [Epub ahead of print]220(1):

A non-canonical Hedgehog pathway initiates ciliogenesis and autophagy.

Tara Akhshi, William S Trimble.

Primary cilia function as critical signaling hubs whose absence leads to severe disorders collectively known as ciliopathies; our knowledge of ciliogenesis remains limited. We show that Smo induces ciliogenesis through two distinct yet essential noncanonical Hh pathways in several cell types, including neurons. Surprisingly, ligand activation of Smo induces autophagy via an LKB1-AMPK axis to remove the satellite pool of OFD1. This is required, but not sufficient, for ciliogenesis. Additionally, Smo activates the Gαi-LGN-NuMA-dynein axis, causing accumulation of a portion of OFD1 at centrioles in early ciliogenesis. Both pathways are critical for redistribution of BBS4 from satellites to centrioles, which is also mediated by OFD1 centriolar translocation. Notably, different Smo agonists, which activate Smo distinctly, activate one or the other of these pathways; only in combination they recapitulate the activity of Hh ligand. These studies provide new insight into physiological stimuli (Hh) that activate autophagy and promote ciliogenesis and introduce a novel role for the Gαi-LGN-NuMA-dynein complex in this process.

DOI: https://doi.org/10.1083/jcb.202004179
J Endourol. 2020 Dec 02.

Percutaneous nephrolithotomy under X ray free technique in upper urinary stone patients with autosomal dominant polycystic kidney disease: experience from a large-volume stone management center.

Bo Xiao, Gang Zhang, Chaoyue Ji, Song Jin, Weiguo Hu, Wenjie Bai, Yuzhe Tang, Jianxing Li.

Objectives To present our large single-center experience in the management of autosomal dominant polycystic kidney disease (ADPKD) with total ultrasound (US)-guided percutaneous nephrolithotomy (PNL) and to evaluate the role of PNL under US in these patients. Patients and methods We retrospectively reviewed the charts of patients with ADPKD who underwent PNL from August 2011 to December 2019. A total of 56 patients were included in this study; all procedures were completed by the total US-guided technique. Demographic characteristics, operative parameters, and postoperative data were collected and analyzed. Results Successful renal access was achieved in all patients. The mean stone size was 3.1 cm (range 1.7-6.5 cm). The initial stone-free rate was 70.6% (36/51); five patients required second-look percutaneous nephrolithotomy to remove residual stones. The other patients underwent oral medication therapy. No severe intraoperative complications occurred; one patient received selective embolization for bleeding on the contralateral side, and one patient needed percutaneous drainage for perinephric abscess. Clavien I or II complications were seen in nine patients. Renal function was improved or stable in most patients; the condition of only one patient deteriorated after surgery. Conclusion Total US-guided PNL is a safe and efficient treatment for kidney stones in patients with ADPKD; perioperative renal function was not adversely affected and complications were acceptable compared with patients in the general population.

DOI: https://doi.org/10.1089/end.2020.0827
Pharmaceutics. 2020 Nov 26. pii: E1147. [Epub ahead of print]12(12):

Semi-Mechanistic Pharmacokinetic Model to Guide the Dose Selection of Nimotuzumab in Patients with Autosomal Dominant Polycystic Kidney Disease.

Niurys de Castro-Suárez, Mirjam N Trame, Mayra Ramos-Suzarte, José M Dávalos, Raymed A Bacallao-Mendez, Anaelys R Maceo-Sinabele, Víctor Mangas-Sanjuán, Gledys Reynaldo-Fernández, Leyanis Rodríguez-Vera.

  Autosomal dominant polycystic kidney disease (ADPKD) is a genetic disease characterized by an overexpression of epidermal growth factor receptor (EGFR). Nimotuzumab is a recombinant humanized monoclonal antibody against human EGFR. The aim of this study was to develop a population pharmacokinetic model for nimotuzumab and to identify demographic and clinical predictive factors of the pharmacokinetic variability. The population pharmacokinetics (PopPK) of nimotuzumab was characterized using a nonlinear mixed-effect modeling approach with NONMEM®. A total of 422 log-transformed concentration-versus-time datapoints from 20 patients enrolled in a single-center phase I clinical trial were used. Quasi steady state approximation of the full TMDD (target-mediated drug disposition) model with constant target concentration best described the concentration-time profiles. A turnover mediator was included which stimulates the non-specific clearance of mAb in the central compartment in order to explain the reduced levels at higher doses. Covariates had no influence on the PK (pharmacokinetics) parameters. The model was able to detect that the maximum effective dose in ADPKD subjects is 100 mg. The developed PopPK model may be used to guide the dose selection for nimotuzumab during routine clinical practice in patients with polycystic kidney disease. The model will further support the ongoing investigations of the PK/PD relationships of nimotuzumab to improve its therapeutic use in other disease areas.

Keywords:  EGFR; NONMEM; autosomal dominant polycystic kidney disease; nimotuzumab; population analysis; semi-mechanistic pharmacokinetics

DOI:  https://doi.org/10.3390/pharmaceutics12121147
Sci Rep. 2020 Dec 03. 10(1): 21018

Proline-rich tyrosine kinase 2 mediates transforming growth factor-beta-induced hepatic stellate cell activation and liver fibrosis.

Jonghwa Kim, Wonseok Kang, So Hee Kang, Su Hyun Park, Ji Young Kim, Sera Yang, Sang Yun Ha, Yong-Han Paik.

Hepatic fibrogenesis is characterized by activation of hepatic stellate cells (HSCs) and accumulation of extracellular matrix (ECM). The impact of ECM on TGF-β-mediated fibrogenic signaling pathway in HSCs has remained obscure. We studied the role of non-receptor tyrosine kinase focal adhesion kinase (FAK) family members in TGF-β-signaling in HSCs. We used a CCl4-induced liver fibrosis mice model to evaluate the effect of FAK family kinase inhibitors on liver fibrosis. RT-PCR and Western blot were used to measure the expression of its target genes; α-SMA, collagen, Nox4, TGF-β1, Smad7, and CTGF. Pharmacological inhibitors, siRNA-mediated knock-down, and plasmid-based overexpression were adopted to modulate the function and the expression level of proteins. Association of PYK2 activation with liver fibrosis was confirmed in liver samples from CCl4-treated mice and patients with significant fibrosis or cirrhosis. TGF-β treatment up-regulated expression of α-SMA, type I collagen, NOX4, CTGF, TGF-β1, and Smad7 in LX-2 cells. Inhibition of FAK family members suppressed TGF-β-mediated fibrogenic signaling. SiRNA experiments demonstrated that TGF-β1 and Smad7 were upregulated via Smad-dependent pathway through FAK activation. In addition, CTGF induction was Smad-independent and PYK2-dependent. Furthermore, RhoA activation was essential for TGF-β-mediated CTGF induction, evidenced by using ROCK inhibitor and dominant negative RhoA expression. We identified that TGF-β1-induced activation of PYK2-Src-RhoA triad leads to YAP/TAZ activation for CTGF induction in liver fibrosis. These findings provide new insights into the role of focal adhesion molecules in liver fibrogenesis, and targeting PYK2 may be an attractive target for developing novel therapeutic strategies for the treatment of liver fibrosis.

DOI: https://doi.org/10.1038/s41598-020-78056-0
Mol Ther. 2020 Nov 25. pii: S1525-0016(20)30607-9. [Epub ahead of print]

Single-Base Resolution: Increasing the Specificity of the CRISPR-Cas System in Gene Editing.

Roy Rabinowitz, Daniel Offen.

The CRISPR-Cas system holds a great promise in the treatment of diseases caused by genetic variations. The Cas protein, an RNA-guided programmable nuclease, generates a double-strand break at precise genomic loci. However, employing the CRISPR-Cas system to distinguish between single-nucleotide variations is challenging. The promiscuity of the guide-RNA (gRNA) and its mismatch tolerance make allele-specific targeting an elusive goal. This review presents a meta-analysis of previous studies reporting position-dependent mismatch tolerance within the gRNA. We also examine the conservativity of the seed sequence, a region within the gRNA with stringent sequence dependency, and propose the existence of a sub-region within the seed sequence with a higher degree of specificity. In addition, we summarize the reports on high-fidelity Cas nucleases with improved specificity, and compare the standard gRNA design methodology to the SNP-derived PAM approach, an alternative method for allele-specific targeting. Combining the two methods may be advantageous in designing CRISPR based therapeutics and diagnostics for heterozygous patients.

DOI: https://doi.org/10.1016/j.ymthe.2020.11.009