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Renal cortical hydrogen peroxide (H 2 O 2 ) stimulates renin release from juxtaglomerular (JG) cells and increases blood pressure: Role of JG cell NOX4
Author(s) -
Hypertension Mariela Mendez.,
Division Vascular Reasearch
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.1218.7
Subject(s) - renin–angiotensin system , renal cortex , medicine , endocrinology , blood pressure , kidney , chemistry , plasma renin activity , stimulation
Renin plays an essential role in blood pressure control and the development of hypertension. Enhanced hydrogen peroxide (H 2 O 2 ) levels in the kidney are associated with hypertension. This is thought to be due to direct stimulation of tubular salt transport and enhanced vascular reactivity. However, we previously found that H 2 O 2 can directly stimulate renin release from renal juxtaglomerular (JG) cells suggesting that this pathway may also be responsible for the hypertension. However, it is not clear whether enhanced H 2 O 2 in the renal cortex stimulates renin release and increases blood pressure. We hypothesized that enhancing renal cortical H 2 O 2 stimulates renin release and increases blood pressure. To enhance renal cortical H 2 O 2 in mice, we placed a subcapsular renal catheter connected to an osmotic minipump to reach a concentration of 1 μM, and measured blood pressure by radio telemetry and plasma renin concentration (PRC). Two days after infusion of H 2 O 2 , systolic blood pressure increased by 22±2 mmHg (p<0.05) and PRC doubled (from 110± 7 to 214±39 ngAngI/hr/ml, p<0.05). In control mice, with renal cortical infusion of saline, blood pressure and PRC were not different from baseline, indicating that renal cortical H 2 O 2 increased renin release and blood pressure. In vivo , H 2 O 2 produced by surrounding cells or endogenously produced, could enhance renin release. We found that in freshly isolated mouse JG cells, decreasing endogenous H 2 O 2 with catalase (100U/ml) decreased baseline renin release by 45±9% ( n = 6; p < 0.05) indicating that endogenously produced H 2 O 2 tonically stimulates renin release. To start dissecting the enzymatic sources of H 2 O 2 production, we studied the NADPH oxidase isoforms present in JG cells. By Western blot, we found that NOX1, NOX2 and NOX4 are expressed in JG cell lysates (n=3). By immunofluorescence and confocal imaging, we observed that NOX4 isoform is highly expressed in JG cell renin granules (n=3). Treating JG cells with apocynin (120 μM), a general inhibitor of NADPH oxidases, decreased renin release by 28±7% (p<0.04). To identify whether NOX4 mediates the endogenous H 2 O 2 production, we used adenovirus mediated gene silencing of NOX4. Silencing NOX4 in JG cells decreased renin release by 34 ±4% ( p < 0.05). We concluded that renal cortical H 2 O 2 is a potent stimuli for renin release in vivo. Endogenously produced H 2 O 2 from NOX4 expressed in mouse JG cells stimulates renin release. Our data suggest that enhanced renal cortical reactive oxygen species may induce hypertension by enhancing renin release. NOX4 inhibition in JG cells might be a candidate for renin release and blood pressure control. Support or Funding Information SDG12070304; RO3DK105300‐01