Proton channels and renal hypertensive injury: a key piece of the Dahl salt-sensitive rat puzzle?

O’Connor, Paul; Guha, Avirup; Stilphen, Carly A.; Sun, Jingping; Jin, Chunhua

doi:10.1152/ajpregu.00115.2015

Cited by 9 publications

(8 citation statements)

References 75 publications

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“…; O'Connor et al. ). Moreover, in both renal tubular epithelial cells and peritoneal macrophages, Hv1‐dependent ROS production was enhanced by low intracellular Na + or by NHE‐1 inhibition (Jin et al.…”

Section: Discussionmentioning

confidence: 99%

Neurovascular protection in voltage‐gated proton channel Hv1 knock‐out rats after ischemic stroke: interaction with Na ⁺ /H ⁺ exchanger‐1 antagonism

Ward

Dong

et al. 2019

Physiol Rep

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Experimental studies have demonstrated protective effects of NHE ‐1 inhibition on cardiac function; however, clinical trials utilizing NHE ‐1 antagonists found an increase in overall mortality attributed to thromboembolic strokes. NADPH oxidase‐derived reactive oxygen species ( ROS ) from microglial cells have been shown to contribute to injury following stroke. We have recently demonstrated that NHE ‐1 inhibition enhances ROS in macrophages in a Hv1‐dependent manner. As Hv1 protein is highly expressed in microglia, we hypothesized that “ NHE ‐1 inhibition may augment neurovascular injury by activating Hv1,” providing a potential mechanism for the deleterious effects of NHE ‐1. The goal of this study was to determine whether neurovascular injury and functional outcomes after experimental stroke differed in wild‐type and Hv1 mutant Dahl salt‐sensitive rats treated with an NHE ‐1 inhibitor. Stroke was induced using both transient and permanent of middle cerebral artery occlusion ( MCAO ). Animals received vehicle or NHE ‐1 inhibitor KR 32568 (2 mg/kg, iv) either 30 min after the start of MCAO or were pretreated (2 mg/kg, iv, day) for 3 days and then subjected to MCAO . Our data indicate that Hv1 deletion confers both neuronal and vascular protection after ischemia. In contrast to our hypothesis, inhibition of NHE ‐1 provided further protection from ischemic stroke, and the beneficial effects of both pre‐ and post‐treatment with KR 32568 were similar in wild‐type and Hv1 −/− rats. These data indicate that Hv1 activation is unlikely to be responsible for the increased incidence of cerebrovascular events observed in the heart disease patients after NHE ‐1 inhibition treatment.

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Section: Discussionmentioning

confidence: 99%

Neurovascular protection in voltage‐gated proton channel Hv1 knock‐out rats after ischemic stroke: interaction with Na ⁺ /H ⁺ exchanger‐1 antagonism

Ward

Dong

et al. 2019

Physiol Rep

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“…Given the known biophysical characteristics of Hv1 5 , localization of this channel to the outer-mitochondrial membrane may provide explanation for the seemingly low activation threshold required to observe functional effects of Hv1 in mTAL. That is, by residing on a membrane with low potential difference, mitochondrial Hv1 may open more easily than Hv1 localized to the cell membrane where membrane potential is −60 to −80mV in mTAL [15]. Both NH 4 Cl loading and osmotic stress appeared to increase mitochondrial membrane potential in mTAL from wild-type animals.…”

Section: Discussionmentioning

confidence: 99%

“…Stimulation of mTAL ROS production by osmotic stress : We have previously shown that osmotic stress promotes ROS production in mTAL [11]. We have utilized this stimuli to identify differences in mTAL ROS production between Dahl salt-sensitive rats and salt-resistant resistant control strains [11], and this stimuli was utilized to identify Hv1 as critical to the formation of ROS production in mTAL [15]. Given this, to investigate the molecular source of Hv1 dependent ROS production in mTAL, we investigated the incrementing bath NaCl concentration on ROS production in mTAL from male wild-type (n = 6), NOX4 −/− (n = 7) and p67phox −/- (n = 7) Dahl salt-sensitive rats.…”

Section: Methodsmentioning

confidence: 99%

Voltage gated proton channels modulate mitochondrial reactive oxygen species production by complex I in renal medullary thick ascending limb

et al. 2019

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Hv1 is a voltage-gated proton channel highly expressed in immune cells where, it acts to maintain NAD(P)H oxidase activity during the respiratory burst. We have recently reported that Hv1 is expressed in cells of the medullary thick ascending limb (mTAL) of the kidney and is critical to augment reactive oxygen species (ROS) production by this segment. While Hv1 is associated with NOX2 mediated ROS production in immune cells, the source of the Hv1 dependent ROS in mTAL remains unknown. In the current study, the rate of ROS formation was quantified in freshly isolated mTAL using dihydroethidium and ethidium fluorescence. Hv1 dependent ROS production was stimulated by increasing bath osmolality and ammonium chloride (NH4Cl) loading. Loss of either p67phox or NOX4 did not abolish the formation of ROS in mTAL. Hv1 was localized to mitochondria within mTAL, and the mitochondrial superoxide scavenger mitoTEMPOL reduced ROS formation. Rotenone significantly increased ROS formation and decreased mitochondrial membrane potential in mTAL from wild-type rats, while treatment with this inhibitor decreased ROS formation and increased mitochondrial membrane potential in mTAL from Hv1−/− mutant rats. These data indicate that NADPH oxidase is not the primary source of Hv1 dependent ROS production in mTAL. Rather Hv1 localizes to the mitochondria in mTAL and modulates the formation of ROS by complex I. These data provide a potential explanation for the effects of Hv1 on ROS production in cells independent of its contribution to maintenance of cell membrane potential and intracellular pH.

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“…ROS can regulate ion transport 16–18,23,35–64 . Superoxide, produced by NADPH oxidase, enhances NaCl transport in the renal proximal tubule 16,17,39,44,45,59 , thick ascending limb of Henle 41,46,48 , and collecting duct 18,47,48 . The voltage-gated proton channel participates in the increased production of superoxide in the renal outer medulla of Dahl salt-sensitive rats 46 .…”

Section: Introductionmentioning

confidence: 99%

“…Superoxide, produced by NADPH oxidase, enhances NaCl transport in the renal proximal tubule 16,17,39,44,45,59 , thick ascending limb of Henle 41,46,48 , and collecting duct 18,47,48 . The voltage-gated proton channel participates in the increased production of superoxide in the renal outer medulla of Dahl salt-sensitive rats 46 . It should be born in mind, however, that ROS can inhibit Na + /K + -ATPase and NHE3 activity in the renal proximal tubule 48,50–53 .…”

Section: Introductionmentioning

confidence: 99%

Genetic polymorphisms associated with reactive oxygen species and blood pressure regulation

2019

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Hypertension is the most prevalent cause of cardiovascular disease and kidney failure but only about 50% of patients achieve adequate blood pressure control, in part, due to inter-individual genetic variations in the response to antihypertensive medication. Significant strides have been made toward the understanding of the role of reactive oxygen species (ROS) in the regulation of the cardiovascular system. However, the role of ROS in human hypertension is still unclear. Polymorphisms of some genes involved in the regulation of ROS production are associated with hypertension, suggesting their potential influence on blood pressure control and response to antihypertensive medication. This review provides an update on the genes associated with the regulation of ROS production in hypertension and discusses the controversies on the use of antioxidants in the treatment of hypertension, including the antioxidant effects of antihypertensive drugs.

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Proton channels and renal hypertensive injury: a key piece of the Dahl salt-sensitive rat puzzle?

Abstract: O'Connor PM, Guha A, Stilphen CA, Sun J, Jin C. Proton channels and renal hypertensive injury: a key piece of the Dahl salt-sensitive rat puzzle? Am J Physiol

Cited by 9 publications

References 75 publications

Neurovascular protection in voltage‐gated proton channel Hv1 knock‐out rats after ischemic stroke: interaction with Na ⁺ /H ⁺ exchanger‐1 antagonism

Neurovascular protection in voltage‐gated proton channel Hv1 knock‐out rats after ischemic stroke: interaction with Na ⁺ /H ⁺ exchanger‐1 antagonism

Voltage gated proton channels modulate mitochondrial reactive oxygen species production by complex I in renal medullary thick ascending limb

Genetic polymorphisms associated with reactive oxygen species and blood pressure regulation

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Proton channels and renal hypertensive injury: a key piece of the Dahl salt-sensitive rat puzzle?

Abstract: O'Connor PM, Guha A, Stilphen CA, Sun J, Jin C. Proton channels and renal hypertensive injury: a key piece of the Dahl salt-sensitive rat puzzle? Am J Physiol

Cited by 9 publications

References 75 publications

Neurovascular protection in voltage‐gated proton channel Hv1 knock‐out rats after ischemic stroke: interaction with Na + /H + exchanger‐1 antagonism

Neurovascular protection in voltage‐gated proton channel Hv1 knock‐out rats after ischemic stroke: interaction with Na + /H + exchanger‐1 antagonism

Voltage gated proton channels modulate mitochondrial reactive oxygen species production by complex I in renal medullary thick ascending limb

Genetic polymorphisms associated with reactive oxygen species and blood pressure regulation

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Resources

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Neurovascular protection in voltage‐gated proton channel Hv1 knock‐out rats after ischemic stroke: interaction with Na ⁺ /H ⁺ exchanger‐1 antagonism

Neurovascular protection in voltage‐gated proton channel Hv1 knock‐out rats after ischemic stroke: interaction with Na ⁺ /H ⁺ exchanger‐1 antagonism