HV1 ACTS AS A SODIUM SENSOR AND PROMOTES SUPEROXIDE PRODUCTION IN MEDULLARY THICK ASCENDING LIMB OF DAHL SALT-SENSITIVE RATS
| Autor: | Howard J. Jacob, Chunhua Jin, Brent Bermingham, Carly A. Stilphen, Nevin A. Lambert, Paul M. O'Connor, Hiram Ocasio, Jingping Sun, Aron M. Geurts, Roshan Patel, Susan M.E. Smith, Avirup Guha, Sandipkumar Darji |
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| Jazyk: | angličtina |
| Rok vydání: | 2014 |
| Předmět: |
Male
medicine.medical_specialty Patch-Clamp Techniques Sodium Intracellular pH chemistry.chemical_element Nephron Article Ion Channels Rats Mutant Strains chemistry.chemical_compound Superoxides Internal medicine Internal Medicine medicine Loop of Henle Animals chemistry.chemical_classification Reactive oxygen species Rats Inbred Dahl Superoxide Hydrogen-Ion Concentration Rats Disease Models Animal Endocrinology medicine.anatomical_structure chemistry Biochemistry Hypertension Kidney Diseases Reactive Oxygen Species Nicotinamide adenine dinucleotide phosphate Intracellular NADP Hydrogen |
| Popis: | 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.13 BN ) 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 salt-sensitive 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 NH 4 Cl prepulse in 0 sodium/BaCl 2 containing media resulted in superoxide production in thick limb from wild-type but not HV1 −/− rats ( P I 0.005 versus 0.002 U/s, P =0.046, respectively). Superoxide production was enhanced by low intracellular sodium (−/− 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. |
| Databáze: | OpenAIRE |
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