Targeted renal knockdown of Na+/H+exchanger regulatory factorSip1produces uric acid nephrolithiasis inDrosophila
| Autor: | Julian A. T. Dow, Selim Terhzaz, Michael F. Romero, Shireen A. Davies, Pablo Cabrero, Saurav Ghimire |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Sodium-Hydrogen Exchangers Physiology Allopurinol 030232 urology & nephrology Uric acid stones Malpighian Tubules urologic and male genital diseases Nephrolithiasis Uric acid nephrolithiasis 03 medical and health sciences 0302 clinical medicine Na+-H+ exchanger-regulatory factor medicine Animals Enzyme Inhibitors Drosophila (subgenus) Gene knockdown Kidney biology Chemistry Microfilament Proteins fungi Phosphoproteins biology.organism_classification Pathophysiology Uric Acid 3. Good health Cell biology Disease Models Animal Drosophila melanogaster 030104 developmental biology medicine.anatomical_structure Gene Knockdown Techniques Mutation Drosophila Research Article |
| Zdroj: | American Journal of Physiology-Renal Physiology Am J Physiol Renal Physiol |
| ISSN: | 1522-1466 1931-857X |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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