Abstract
The antidiuretic hormone vasopressin (AVP), acting through its type 2 receptor (V2R) in the collecting duct (CD), critically controls urine concentrating capability. Here, we report that site-1 protease-derived (S1P-derived) soluble (pro)renin receptor (sPRR) participates in regulation of fluid homeostasis via targeting V2R. In cultured inner medullary collecting duct (IMCD) cells, AVP-induced V2R expression was blunted by a PRR antagonist, PRO20; a PRR-neutralizing antibody; or a S1P inhibitor, PF-429242. In parallel, sPRR release was increased by AVP and reduced by PF-429242. Administration of histidine-tagged sPRR, sPRR-His, stimulated V2R expression and also reversed the inhibitory effect of PF-429242 on the expression induced by AVP. PF-429242 treatment in C57/BL6 mice impaired urine concentrating capability, which was rescued by sPRR-His. This observation was recapitulated in mice with renal tubule-specific deletion of S1P. During the pharmacological or genetic manipulation of S1P alone or in combination with sPRR-His, the changes in urine concentration were paralleled with renal expression of V2R and aquaporin-2 (AQP2). Together, these results support that S1P-derived sPRR exerts a key role in determining renal V2R expression and, thus, urine concentrating capability.
Keywords:
Nephrology; Transport.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Animals
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Antidiuretic Hormone Receptor Antagonists / pharmacology
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Aquaporin 2 / genetics
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Cells, Cultured
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Epithelial Cells
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Kidney Concentrating Ability / drug effects
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Kidney Concentrating Ability / physiology*
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Kidney Tubules, Collecting / cytology
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Kidney Tubules, Collecting / drug effects
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Kidney Tubules, Collecting / metabolism*
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Male
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Mice
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Mice, Knockout
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Models, Animal
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Peptide Fragments / pharmacology
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Primary Cell Culture
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Proprotein Convertases / antagonists & inhibitors
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Proprotein Convertases / genetics
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Proprotein Convertases / metabolism
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Proton-Translocating ATPases / metabolism*
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Pyrrolidines / pharmacology
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Rats
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Receptors, Cell Surface / metabolism*
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Receptors, Vasopressin / genetics
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Receptors, Vasopressin / metabolism*
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Renin / metabolism
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Renin / pharmacology
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Serine Endopeptidases / genetics
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Serine Endopeptidases / metabolism
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Urothelium / cytology
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Vacuolar Proton-Translocating ATPases
Substances
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ATP6AP2 protein, mouse
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Antidiuretic Hormone Receptor Antagonists
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Aqp2 protein, mouse
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Aquaporin 2
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Avpr2 protein, mouse
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Avpr2 protein, rat
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PF-429242
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PRO20 peptide
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Peptide Fragments
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Pyrrolidines
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Receptors, Cell Surface
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Receptors, Vasopressin
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Proprotein Convertases
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Serine Endopeptidases
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membrane-bound transcription factor peptidase, site 1
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Renin
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ATP6AP2 protein, rat
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Vacuolar Proton-Translocating ATPases
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Proton-Translocating ATPases