HV1 acts as a sodium sensor and promotes superoxide production in medullary thick ascending limb of Dahl salt-sensitive rats

Chunhua Jin, Jingping Sun, Carly A. Stilphen, Susan M.E. Smith, Hiram Ocasio, Brent Bermingham, Sandip Darji, Avirup Guha, Roshan Patel, Aron M. Geurts, Howard J. Jacob, Nevin A. Lambert, Paul M. O'Connor

Research output: Contribution to journalArticlepeer-review

17 Scopus citations


We previously characterized a H+ transport pathway in medullary thick ascending limb nephron segments that when activated stimulated the production of superoxide by nicotinamide adenine dinucleotide phosphate oxidase. Importantly, the activity of this pathway was greater in Dahl salt-sensitive rats than salt-resistant (SS.13BN) rats, and superoxide production was enhanced in low Na+ media. The goal of this study was to determine the molecular identity of this pathway and its relationship to Na+. We hypothesized that the voltage-gated proton channel, HV1, was the source of superoxide-stimulating H+ currents. To test this hypothesis, we developed HV1-/- null mutant rats on the Dahl saltsensitive rat genetic background using zinc-finger nuclease gene targeting. HV1 could be detected in medullary thick limb from wild-type rats. Intracellular acidification using an NH4Cl prepulse in 0 sodium/BaCl2 containing media resulted in superoxide production in thick limb from wild-type but not HV1-/- rats (P<0.05) and more rapid recovery of intracellular pH in wild-type rats (ΔpHI 0.005 versus 0.002 U/s, P=0.046, respectively). Superoxide production was enhanced by low intracellular sodium (<10 mmol/L) in both thick limb and peritoneal macrophages only when HV1 was present. When fed a high-salt diet, blood pressure, outer medullary renal injury (tubular casts), and oxidative stress (4-hydroxynonenal staining) were significantly reduced in HV1-/-rats compared with wild-type Dahl salt-sensitive rats. We conclude that HV1 is expressed in medullary thick ascending limb and promotes superoxide production in this segment when intracellular Na+ is low. HV1 contributes to the development of hypertension and renal disease in Dahl salt-sensitive rats.

Original languageEnglish (US)
Pages (from-to)541-550
Number of pages10
Issue number3
StatePublished - Sep 2014


  • Free radicals
  • Hypertension
  • Oxidative stress

ASJC Scopus subject areas

  • Internal Medicine


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