title: Antihypertensive and renoprotective effect of the kinin pathway activated by potassium in a model of salt sensitivity following overload proteinuria.
abstract: The albumin overload model induces proteinuria and tubulointersitial damage, followed by hypertension when rats are exposed to a hypersodic diet. To understand the effect of kinin system stimulation on salt-sensitive hypertension and to explore its potential renoprotective effects, the model was induced in Sprague-Dawley rats that had previously received a high-potassium diet to enhance activity of the kinin pathway, followed with/without administration of icatibant to block the kinin B₂ receptor (B₂R). A disease control group received albumin but not potassium or icatibant, and all groups were exposed to a hypersodic diet to induce salt-sensitive hypertension. Potassium treatment increased the synthesis and excretion of tissue kallikrein (Klk1/rKLK1) accompanied by a significant reduction in blood pressure and renal fibrosis and with downregulation of renal transforming growth factor-β (TGF-β) mRNA and protein compared with rats that did not receive potassium. Participation of the B₂R was evidenced by the fact that all beneficial effects were lost in the presence of the B₂R antagonist. In vitro experiments using the HK-2 proximal tubule cell line showed that treatment of tubular cells with 10 nM bradykinin reduced the epithelial-mesenchymal transdifferentiation and albumin-induced production of TGF-β, and the effects produced by bradykinin were prevented by pretreatment with the B₂R antagonist. These experiments support not only the pathogenic role of the kinin pathway in salt sensitivity but also sustain its role as a renoprotective, antifibrotic paracrine system that modulates renal levels of TGF-β.
authors.affiliation: Department of Nephrology, Universidad Austral de Chile, Valdivia, Chile. leopoldoardiles@gmail.com
authors.forename: Leopoldo
authors.initials: L
authors.lastname: Ardiles
authors.forename: Areli
authors.initials: A
authors.lastname: Cardenas
authors.forename: María E
authors.initials: ME
authors.lastname: Burgos
authors.forename: Alejandra
authors.initials: A
authors.lastname: Droguett
authors.forename: Pamela
authors.initials: P
authors.lastname: Ehrenfeld
authors.forename: Daniel
authors.initials: D
authors.lastname: Carpio
authors.forename: Sergio
authors.initials: S
authors.lastname: Mezzano
authors.forename: Carlos D
authors.initials: CD
authors.lastname: Figueroa
mesh_terms: D000818:Animals; D001920:Bradykinin / Q000031:analogs & derivatives* / Q000494:pharmacology; D065094:Bradykinin B2 Receptor Antagonists; D002460:Cell Line; D005260:Female; D005355:Fibrosis / Q000517:prevention & control*; D006801:Humans; D006973:Hypertension / Q000188:drug therapy* / Q000503:physiopathology; D007674:Kidney Diseases / Q000473:pathology / Q000517:prevention & control*; D007684:Kidney Tubules / Q000473:pathology; D007705:Kinins / Q000502:physiology*; D053858:Metabolic Networks and Pathways / Q000187:drug effects / Q000502:physiology; D017419:Potassium, Dietary / Q000494:pharmacology*; D011507:Proteinuria / Q000139:chemically induced / Q000503:physiopathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012710:Serum Albumin, Bovine; D017673:Sodium Chloride, Dietary / Q000009:adverse effects; D020840:Tissue Kallikreins / Q000652:urine; D016212:Transforming Growth Factor beta / Q000096:biosynthesis / Q000502:physiology*
chemical_list: D065094:Bradykinin B2 Receptor Antagonists; D007705:Kinins; D017419:Potassium, Dietary; D017673:Sodium Chloride, Dietary; D016212:Transforming Growth Factor beta; D012710:Serum Albumin, Bovine; C065679:icatibant; D020840:Tissue Kallikreins; D001920:Bradykinin
keywords: TGF-β; bradykinin; bradykinin B2 receptor; kallikrein; potassium; renoprotection