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1 Hypertension & Vascular Research, Henry Ford Hospital, Detroit, Michigan, United States
* To whom correspondence should be addressed. E-mail: rliu1{at}hfhs.org.
Superoxide (O2-) enhances tubuloglomerular feedback by scavenging nitric oxide at the macula densa. However, the singling pathway of O2- production in the macula densa is not known. We hypothesized that the increase in tubular NaCl concentration that initiates tubuloglomerular feedback induces O2- production. We microperfused the thick ascending limb and attached macula densa in rabbits. A fluorescent dye, dihydroethidium, was used to detect O2- at the macula densa. When luminal NaCl was switched from 10 to 80 mM, O2- significantly increased. To make sure that the shifts in the oxyethidium/dihydroethidium ratio were due to changes in O2- , we used Tempol and found that the increase in the fluorescent ratio was blocked in the presence of tempol. To determine the source of O2-, we used the NAD(P)H oxidase inhibitor apocynin. When luminal NaCl was switched from 10 to 80 mM in the presence of apocynin, O2- production was inhibited by 80%. To see if the effect of increasing luminal NaCl involves Na/K/2Cl cotransporters, we inhibited them with furosemide. When luminal NaCl was switched from 10 to 80 mM in the presence of furosemide, O2- production was blocked. To test whether depolarization of the macula densa induces O2- production, we artificially induced depolarization by adding valinomycin (10-6 M) and 25 mM KCl to the luminal perfusate. Depolarization alone significantly increases O2- production. We conclude that increasing luminal NaCl induces O2- production during tubuloglomerular feedback. O2- generated by the macula densa is primarily derived from NAD(P)H oxidase and is induced by depolarization.
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