Targeted renal knockdown of Na+/H+ exchanger regulatory factor Sip1 produces uric acid nephrolithiasis in Drosophila

Ghimire, S., Terhzaz, S. , Cabrero, P. , Romero, M. F., Davies, S. and Dow, J. A.T. (2019) Targeted renal knockdown of Na+/H+ exchanger regulatory factor Sip1 produces uric acid nephrolithiasis in Drosophila. American Journal of Physiology: Renal Physiology, 317(4), F930-F940. (doi: 10.1152/ajprenal.00551.2018) (PMID:31364377) (PMCID:PMC6843049)

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Nephrolithiasis is one of the most common kidney diseases with poorly understood pathophysiology, but experimental study has been hindered by lack of experimentally tractable models. Drosophilamelanogaster is a useful model organism for renal diseases because of genetic and functional similarities of Malpighian (renal) tubules with the human kidney. Here, we demonstrate the function of Sip1 (SRY-interacting protein 1) gene, an orthologue of human NHERF1 in Drosophila MTs, and its impact on nephrolithiasis. Abundant birefringent calculi were observed in Sip1 mutant flies, and the phenotype was also observed in renal stellate cell-specific RNAi Sip1 knockdowns in otherwise normal flies, confirming a renal aetiology. This phenotype was abolished in rosy flies (which model human xanthinuria) and by the xanthine oxidase inhibitor allopurinol, suggesting that the calculi were of uric acid. This was confirmed by direct assay for urate. Stones rapidly dissolved when the tubule was bathed in alkaline media, suggesting that Sip1 knockdown was acidifying the tubule. SIP1 was shown to co-locate with Na+/H+ exchanger NHE2, and with moesin, in stellate cells; and so a model was developed in which Sip1 normally regulates NHE2 activity and thus luminal pH. Drosophila renal tubule thus offers a useful model for urate nephrolithiasis.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Cabrero, Mr Pablo and Dow, Professor Julian and Terhzaz, Dr Selim and Ghimire, Mr Saurav and Davies, Professor Shireen
Authors: Ghimire, S., Terhzaz, S., Cabrero, P., Romero, M. F., Davies, S., and Dow, J. A.T.
College/School:College of Medical Veterinary and Life Sciences > Institute of Molecular Cell and Systems Biology
College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing
Journal Name:American Journal of Physiology: Renal Physiology
Publisher:American Physiological Society
ISSN (Online):1522-1466
Published Online:25 September 2019
Copyright Holders:Copyright © 2019 the American Physiological Society
First Published:First published in American Journal of Physiology: Renal Physiology 317(4):F930-F940
Publisher Policy:Reproduced in accordance with the publisher copyright policy

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
669961RENALTRACTShireen DaviesEuropean Commission (EC)642937RI MOLECULAR CELL & SYSTEMS BIOLOGY
626691Functional Genomics of the enigmatic stellate cell.Shireen DaviesBiotechnology and Biological Sciences Research Council (BBSRC)BB/L002647/1RI MOLECULAR CELL & SYSTEMS BIOLOGY
538314Drosophila model of oxalate nephrolithiasisJulian DowNational Institutes of Health (NIH)R01DK092408RI MOLECULAR CELL & SYSTEMS BIOLOGY
626471Improving stone disease treatment by accurate phenotyping and risk stratificationJulian DowNational Institute of Health (NIH-BETH)1U54DK100227-01RI MOLECULAR CELL & SYSTEMS BIOLOGY