The role of sphingolipids in autosomal dominant polycystic kidney disease (ADPKD)

Autosomal dominant polycystic kidney disease (ADPKD) is a genetic disorder characterized by the development of renal cysts and eventual renal failure. There is currently no cure for ADPKD, but various treatments are available to alleviate the symptoms. In ADPKD, cystic renal epithelia are prevalent by the upregulation of various growth regulating signalling pathways, such as ERK-1/2 and PI3K/Akt/mTOR, which leads to elevated kidney epithelial cell proliferation. Dysregulation of their primary cilia (evident by decreased levels of acetylated α-tubulin) is also a crucial factor in defective renal cystic epithelia. Sphingolipids contribute to regulating these cellular processes. Two isoforms of sphingosine kinase (SK1 and SK2) catalyse the formation of the bioactive lipid sphingosine-1-phosphate (S1P) from sphingosine.;We sought to determine the effects of modulating these enzymes, either separately or together, on the signalling pathways implicated in ADPKD. Five novel SK inhibitors (SK2-selective,SK1-selective or dual SK1/SK2 inhibitor) were evaluated. Comparison was made with a glucosylceramide synthase inhibitor (Genz-123346) as blocking the synthesis of glucosylceramide is emerging as a possible therapeutic for ADPKD. The current study shows that the SK2-selective inhibitors, ST-066, ST-081 and HWG-35D, and the dualSK1/SK2 inhibitor, PLR-11, decreased DNA synthesis, PCNA expression, Aktphosphorylation and ERK-1/2 phosphorylation, but had no major effect on apoptosis, autophagy, α-tubulin acetylation or primary cilia in Madin-Darby Canine Kidney(MDCK) cells. Collectively, these data suggest that ST-066, ST-081, HWG-35D andPLR-11 affect signalling pathways of relevance to cyst growth; however, the potential application of SK2 inhibitors in ADPKD therapeutics remains to be determined.

Name dc:type.qualificationname

mres

Level dc:type.qualificationlevel

masters-pg

Grantor dc:publisher.institution

University of Strathclyde

Year dc:date.issued

2020

Author dc:creator

• Wan, Cameron

Advisor dc:contributor.advisor

• Pyne, Susan

DOI

10.48730/frb5-9a04

Identifier

T15818

Author Identifier

201863854

OAI identifier oai:identifier

oai:strathclyde:pn89d6567