title: H2O2 generated by NADPH oxidase 4 contributes to transient receptor potential vanilloid 1 channel-mediated mechanosensation in the rat kidney.
abstract: The presence of NADPH oxidase (Nox) in the kidney, especially Nox4, results in H2O2 production, which regulates Na(+) excretion and urine formation. Redox-sensitive transient receptor potential vanilloid 1 channels (TRPV1s) are distributed in mechanosensory fibers of the renal pelvis and monitor changes in intrapelvic pressure (IPP) during urine formation. The present study tested whether H2O2 derived from Nox4 affects TRPV1 function in renal sensory responses. Perfusion of H2O2 into the renal pelvis dose dependently increased afferent renal nerve activity and substance P (SP) release. These responses were attenuated by cotreatment with catalase or TRPV1 blockers. In single unit recordings, H2O2 activated afferent renal nerve activity in response to rising IPP but not high salt. Western blots revealed that Nox2 (gp91(phox)) and Nox4 are both present in the rat kidney, but Nox4 is abundant in the renal pelvis and originates from dorsal root ganglia. This distribution was associated with expression of the Nox4 regulators p22(phox) and polymerase δ-interacting protein 2. Coimmunoprecipitation experiments showed that IPP increases polymerase δ-interacting protein 2 association with Nox4 or p22(phox) in the renal pelvis. Interestingly, immunofluorescence labeling demonstrated that Nox4 colocalizes with TRPV1 in sensory fibers of the renal pelvis, indicating that H2O2 generated from Nox4 may affect TRPV1 activity. Stepwise increases in IPP and saline loading resulted in H2O2 and SP release, sensory activation, diuresis, and natriuresis. These effects, however, were remarkably attenuated by Nox inhibition. Overall, these results suggest that Nox4-positive fibers liberate H2O2 after mechanostimulation, thereby contributing to a renal sensory nerve-mediated diuretic/natriuretic response.
authors.affiliation: Department of Surgery, Liou-Ying Hospital, Chi-Mei Medical Center, Tainan Hsien, Taiwan;
authors.forename: Chian-Shiung
authors.initials: CS
authors.lastname: Lin
authors.affiliation: Department of Urology, Cardinal Tien Hospital, New Taipei, Taiwan;
authors.forename: Shang-Hsing
authors.initials: SH
authors.lastname: Lee
authors.affiliation: Department of Urology, National Cheng Kung University, Tainan, Taiwan;
authors.forename: Ho-Shiang
authors.initials: HS
authors.lastname: Huang
authors.affiliation: Department of Cardiovascular Surgery, National Taiwan University Hospital, Taipei, Taiwan; and.
authors.forename: Yih-Sharng
authors.initials: YS
authors.lastname: Chen
authors.affiliation: School of Medicine, Fu-Jen Catholic University, New Taipei, Taiwan med0041@mail.fju.edu.tw.
authors.forename: Ming-Chieh
authors.initials: MC
authors.lastname: Ma
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D004231:Diuresis; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006861:Hydrogen Peroxide / Q000378:metabolism* / Q000633:toxicity; D007682:Kidney Pelvis / Q000201:enzymology* / Q000294:innervation*; D008465:Mechanoreceptors / Q000187:drug effects / Q000201:enzymology*; D040542:Mechanotransduction, Cellular / Q000187:drug effects; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009318:Natriuresis; D011312:Pressure; D011485:Protein Binding; D017208:Rats, Wistar; D013373:Substance P / Q000378:metabolism; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013997:Time Factors
chemical_list: D002352:Carrier Proteins; D004791:Enzyme Inhibitors; C000593573:Poldip2 protein, rat; D050916:TRPV Cation Channels; C493922:Trpv1 protein, rat; D013373:Substance P; D006861:Hydrogen Peroxide; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C498911:Nox4 protein, rat; C515768:Cyba protein, rat
keywords: NADPH oxidase; diuresis/natriuresis; hydrogen peroxide; mechanoreceptors; renal nerves