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

Saurav Ghimire, Selim Terhzaz, Pablo Cabrero, Michael F. Romero, Shireen A. Davies, Julian A.T. Dow

Research output: Contribution to journalArticle

Abstract

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. Drosophila melanogaster is a useful model organism for renal diseases because of genetic and functional similarities of Malpighian (renal) tubules with the human kidney. Here, we demonstrated function of the sex-determining region Y protein-interacting protein-1 (Sip1) gene, an ortholog of human Na+/H+ exchanger regulatory factor (NHERF1), in Drosophila Malpighian tubules 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 RNA interference Sip1 knockdown in otherwise normal flies, confirming a renal etiology. This phenotype was abolished in rosy mutant 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 biochemical 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 collocate with Na+/H+ exchanger isoform 2 (NHE2) and with moesin in stellate cells. Knockdown of NHE2 specifically to the stellate cells also increased renal uric acid stone formation, and so a model was developed in which SIP1 normally regulates NHE2 activity and luminal pH, ultimately leading to uric acid stone formation. Drosophila renal tubules may thus offer a useful model for urate nephrolithiasis.

Original languageEnglish (US)
Pages (from-to)F930-F940
JournalAmerican journal of physiology. Renal physiology
Volume317
Issue number4
DOIs
StatePublished - Oct 1 2019

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Nephrolithiasis
Uric Acid
Drosophila
Kidney
Sodium-Hydrogen Antiporter
Diptera
Malpighian Tubules
Protein Isoforms
Calculi
Sex-Determining Region Y Protein
Phenotype
Inborn Genetic Diseases
Allopurinol
Xanthine Oxidase
Kidney Diseases
RNA Interference
sodium-hydrogen exchanger regulatory factor
Drosophila melanogaster
Genes

Keywords

  • Drosophila
  • Malpighian tubule
  • nephrolithiasis
  • sex-determining region Y protein-interacting protein-1
  • uric acid stones

ASJC Scopus subject areas

  • Physiology
  • Urology

Cite this

Targeted renal knockdown of Na+/H+ exchanger regulatory factor Sip1 produces uric acid nephrolithiasis in Drosophila. / Ghimire, Saurav; Terhzaz, Selim; Cabrero, Pablo; Romero, Michael F.; Davies, Shireen A.; Dow, Julian A.T.

In: American journal of physiology. Renal physiology, Vol. 317, No. 4, 01.10.2019, p. F930-F940.

Research output: Contribution to journalArticle

Ghimire, Saurav ; Terhzaz, Selim ; Cabrero, Pablo ; Romero, Michael F. ; Davies, Shireen A. ; Dow, Julian A.T. / Targeted renal knockdown of Na+/H+ exchanger regulatory factor Sip1 produces uric acid nephrolithiasis in Drosophila. In: American journal of physiology. Renal physiology. 2019 ; Vol. 317, No. 4. pp. F930-F940.
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