Glycosphingolipid metabolism and polycystic kidney disease

Natoli, Thomas A.; Modur, Vijay; Ibraghimov‐Beskrovnaya, Oxana

doi:10.1016/j.cellsig.2020.109526

Cited by 20 publications

(15 citation statements)

References 105 publications

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“…The highest tested dose of sinbaglustat resulted in a reduction in GlcCer of 72%, which is in line with the data published for other GCS inhibitors 30 . The GCS selective inhibitor venglustat decreased plasma GlcCer in healthy subjects by up to 80% 31 . The dose‐dependent reduction of GlcCer demonstrates target engagement (i.e., inhibition of peripheral GCS by sinbaglustat).…”

Section: Discussionsupporting

confidence: 87%

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Assessment of Target Engagement in a First‐in‐Human Trial with Sinbaglustat, an Iminosugar to Treat Lysosomal Storage Disorders

Géhin

Melchior

Welford

et al. 2020

Clinical Translational Sci

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In this first‐in‐human study, the tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of single and multiple oral doses of sinbaglustat, a dual inhibitor of glucosylceramide synthase (GCS) and non‐lysosomal glucosyl ceramidase (GBA2), were investigated in healthy subjects. The single‐ascending dose (SAD) and multiple‐ascending dose (MAD) studies were randomized, double‐blind, and placebo‐controlled. Single doses from 10 to 2,000 mg in men and multiple doses from 30 to 1,000 mg twice daily for 7 days in male and female subjects were investigated. Tolerability, PK, and PD data were collected up to 3 days after (last) treatment administration and analyzed descriptively. Sinbaglustat was well‐tolerated in the SAD and MAD studies, however, at the highest dose of the MAD, three of the four female subjects presented a similar pattern of general symptoms. In all cohorts, sinbaglustat was rapidly absorbed. Thereafter, plasma concentrations decreased biphasically. In the MAD study, steady‐state conditions were reached on Day 2 without accumulation. During sinbaglustat treatment, plasma concentrations of glucosylceramide (GlcCer), lactosylceramide, and globotriaosylceramide decreased in a dose‐dependent manner, reflecting GCS inhibition. The more complex the glycosphingolipid, the more time was required to elicit PD changes. After treatment stop, GlcCer levels returned to baseline and increased above baseline at lowest doses, probably due to the higher potency of sinbaglustat on GBA2 compared to GCS. Overall, sinbaglustat was welltolerated up to the highest tested doses. The PK profile is compatible with b.i.d. dosing. Sinbaglustat demonstrated target engagement in the periphery for GCS and GBA2.

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Section: Discussionsupporting

confidence: 87%

“…30 The GCS selective inhibitor venglustat decreased plasma GlcCer in healthy subjects by up to 80%. 31 The dose-dependent reduction of GlcCer demonstrates target engagement (i.e., inhibition of peripheral GCS by sinbaglustat). The effect of GCS inhibition appeared to propagate down the GSL pathway, with LacCer and Gb3 also being reduced.…”

Section: Discussionmentioning

confidence: 99%

Assessment of Target Engagement in a First‐in‐Human Trial with Sinbaglustat, an Iminosugar to Treat Lysosomal Storage Disorders

Géhin

Melchior

Welford

et al. 2020

Clinical Translational Sci

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“…After achieving immortalization (P29), the expression of genes associated with the glycosphingolipid biosynthesis pathway was enhanced. The upregulation of glycosphingolipid biosynthetic pathway-related genes has been shown to be associated with the promotion of cell proliferation [ 38 , 39 ]. Thus, it is considered that upregulation of these genes may be involved in the immortalization of CHK cells.…”

Section: Discussionmentioning

confidence: 99%

Novel cell lines derived from Chinese hamster kidney tissue

Kawabe

Kamihira

2022

PLoS ONE

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Immortalized kidney cell lines are widely used in basic and applied research such as cell permeability tests and drug screening. Although many cell lines have been established from kidney tissues, the immortalization process has not been clarified in these cell lines. In this study, we analyzed the phenotypic changes that occurred during the immortalization of kidney cells derived from Chinese hamster tissue in terms of karyotype and gene expression profiles. In the newly established cell line, designated as CHK-Q, gene expression profiles at each stage of the immortalization process and during the adaptation to serum-free conditions were analyzed by DNA microarray. Renal stem cell markers CD24 and CD133 were expressed in CHK-Q cells, suggesting that CHK-Q cells were transformed from renal stem cells. Kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment analysis to identify the pathways of upregulated and downregulated genes revealed that the immortalization of CHK-Q cells was associated with increased fluctuations in the expression of specific proto-oncogenes. Karyotype analysis of spontaneously immortalized CHK-Q cells indicated that CHK-Q chromosomes had a typical modal number of 23 but possessed slight chromosomal abnormalities. In this study, we investigated the mechanism of cell environmental adaptation by analyzing gene expression behavior during the immortalization process and serum-free adaptation. CHK-Q cells are applicable to the fields of biotechnology and biomedical science by utilizing their characteristics as kidney-derived cells.

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“…Activation of rapamycin kinase complex lead to de novo ceramide synthesis and to an increase of glucosylceramide production. Accumulation of glycosphingolipids leads to the loss of cell differentiation and proliferation which promotes cyst growth [ 93 ]. Glucosoceramide plasma levels were found in animal models and treatment with glucosylceramide synthase inhibitors reduced cyst growth [ 94 ].…”

Section: Future Optionsmentioning

confidence: 99%

Autosomal Dominant Polycystic Kidney Disease: From Pathophysiology of Cystogenesis to Advances in the Treatment

Reiterová

Tesař

2022

IJMS

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Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic renal disease, with an estimated prevalence between 1:1000 and 1:2500. It is mostly caused by mutations of the PKD1 and PKD2 genes encoding polycystin 1 (PC1) and polycystin 2 (PC2) that regulate cellular processes such as fluid transport, differentiation, proliferation, apoptosis and cell adhesion. Reduction of calcium ions and induction of cyclic adenosine monophosphate (sAMP) promote cyst enlargement by transepithelial fluid secretion and cell proliferation. Abnormal activation of MAPK/ERK pathway, dysregulated signaling of heterotrimeric G proteins, mTOR, phosphoinositide 3-kinase, AMPK, JAK/STAT activator of transcription and nuclear factor kB (NF-kB) are involved in cystogenesis. Another feature of cystic tissue is increased extracellular production and recruitment of inflammatory cells and abnormal connections among cells. Moreover, metabolic alterations in cystic cells including defective glucose metabolism, impaired beta-oxidation and abnormal mitochondrial activity were shown to be associated with cyst expansion. Although tolvaptan has been recently approved as a drug that slows ADPKD progression, some patients do not tolerate tolvaptan because of frequent aquaretic. The advances in the knowledge of multiple molecular pathways involved in cystogenesis led to the development of animal and cellular studies, followed by the development of several ongoing randomized controlled trials with promising drugs. Our review is aimed at pathophysiological mechanisms in cystogenesis in connection with the most promising drugs in animal and clinical studies.

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Glycosphingolipid metabolism and polycystic kidney disease

Cited by 20 publications

References 105 publications

Assessment of Target Engagement in a First‐in‐Human Trial with Sinbaglustat, an Iminosugar to Treat Lysosomal Storage Disorders

Assessment of Target Engagement in a First‐in‐Human Trial with Sinbaglustat, an Iminosugar to Treat Lysosomal Storage Disorders

Novel cell lines derived from Chinese hamster kidney tissue

Autosomal Dominant Polycystic Kidney Disease: From Pathophysiology of Cystogenesis to Advances in the Treatment

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