Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P47989 (xanthine oxidase)
 8,633 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This study aimed to investigate the effects of reactive oxygen species on the hepatic macrophages, the Kupffer cells (KC), and to identify the relevant targets of vasoconstrictors involved in the regulation of intrahepatic microcirculation and therefore portal pressure. The effects of hydrogen peroxide (H2O2), xanthine/xanthine oxidase or a thromboxane (TX) analogue (U46619; 0.1 microM) were tested in sham-operated and fibrotic livers (bile duct ligation over 4 weeks) during isolated rat liver perfusion and in vivo with or without additional KC blockade (gadolinium chloride, 10 mg kg(-1) body weight, 48 and 24 h, i.p.). To investigate downstream mechanisms, a TXA2 antagonist (BM 13.177; 20 microM) or a Rho kinase inhibitor (Y27632; 10 microM) was infused additionally. TXB2 efflux was measured by enzyme-linked immunosorbent assay. The phosphorylation state of moesin (p-moesin), as indicator for Rho kinase activity, was assessed by Western blot analyses. Portal pressure was dose-dependently increased by H2O2 (maximum, 0.5 mM) and, to a lower extent, by xanthine/xanthine oxidase together with catalase. The portal pressure increase by H2O2 was attenuated by previous KC blockade. TXA2 efflux increased after H2O2 infusion and was reduced by KC blockade. The TXA2 antagonist counteracted the H2O2-induced increase in portal pressure. The Rho kinase inhibitor attenuated portal pressure increase after TXA2 analogue or H2O2 infusion. Hepatic levels of p-moesin were increased after H2O2 infusion. Reactive oxygen species increased portal pressure via stimulation of TXA2 production by KCs and a subsequent Rho kinase-dependent contraction of the intrahepatic vasculature. In conclusion, the KCs that are well known to produce H2O2 could also be activated by H2O2. This vicious cycle may best be interrupted at the earliest time point.
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PMID:Kupffer cell activation by hydrogen peroxide: a new mechanism of portal pressure increase. 2011 78

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.
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PMID:Targeted renal knockdown of Na+/H+ exchanger regulatory factor Sip1 produces uric acid nephrolithiasis in Drosophila. 3227 47