Faculty Collaboration Database

Role of Nox4 and p67phox subunit of Nox2 in ROS production in response to increased tubular flow in the mTAL of Dahl salt-sensitive rats. Am J Physiol Renal Physiol 2016 Aug 01;311(2):F450-8

Date

06/10/2016

Pubmed ID

27279484

Pubmed Central ID

PMC5243222

DOI

10.1152/ajprenal.00187.2016

Scopus ID

2-s2.0-84984629818 (requires institutional sign-in at Scopus site)   29 Citations

Abstract

Nox4 and Nox2 are the most abundant NADPH oxidases (Nox) in the kidney and have been shown to contribute to hypertension, renal oxidative stress, and injury in Dahl salt-sensitive (SS) hypertensive rats. The present study focused on the role of Nox4 and p67phox/Nox2 in the generation of H2O2 and O2 (·-) in the renal medullary thick ascending limb of Henle (mTAL) of SS rats in response to increasing luminal flow (from 5 to 20 nl/min). Nox4 and p67phox/Nox2 genes were found to be expressed in the mTAL of SS rats. Responses of SS rats were compared with those of SS rats with knockout of Nox4 (SS(Nox4-/-)) or functional mutation of p67phox (SS(p67phox-/-)). Nox4 was the dominant source of increased intracellular H2O2 production in response to increased luminal flow as determined using the fluorescent dye peroxyfluor 6-AM (PF6-AM). The rate of mitochondrial H2O2 production [as determined by mitochondria peroxy yellow 1 (mitoPY1)] was also significantly reduced in SS(Nox4-/-) compared with SS rats, but not in SS(p67phox-/-) rats. In contrast, intracellular superoxide (O2 (·-)) production (the ratio of ethidium to dihydroethidium) in the mTAL of SS(Nox4-/-) rats was nearly identical to that of SS rats in response to luminal flow, indicating that Nox4 made no measurable contribution. mTAL O2 (·-) production was reduced in SS(p67phox-/-) compared with SS rats at the lower luminal flow of 5 nl/min and progressively increased when perfusion was changed to 20 nl/min. We conclude that increased mTAL luminal flow results in increases in intracellular and mitochondrial H2O2, which are dependent on the presence of Nox4, and that p67phox/Nox2 accounts solely for increases in O2 (·-) production.

Author List

Zheleznova NN, Yang C, Cowley AW Jr

Author

Allen W. Cowley Jr PhD Professor in the Physiology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Hydrogen Peroxide
Kidney Tubules
Loop of Henle
Male
Membrane Glycoproteins
NADH, NADPH Oxidoreductases
NADPH Oxidase 2
NADPH Oxidase 4
NADPH Oxidases
Nephrons
Rats
Rats, Inbred Dahl
Reactive Oxygen Species