title: Renal (tissue) kallikrein-kinin system in the kidney and novel potential drugs for salt-sensitive hypertension.
abstract: A large variety of antihypertensive drugs, such as angiotensin converting enzyme inhibitors, diuretics, and others, are prescribed to hypertensive patients, with good control of the condition. In addition, all individuals are generally believed to be salt sensitive and, thus, severe restriction of salt intake is recommended to all. Nevertheless, the physiological defense mechanisms in the kidney against excess salt intake have not been well clarified. The present review article demonstrated that the renal (tissue) kallikrein-kinin system (KKS) is ideally situated within the nephrons of the kidney, where it functions to inhibit the reabsorption of NaCl through the activation of bradykinin (BK)-B2 receptors localized along the epithelial cells of the collecting ducts (CD). Kinins generated in the CD are immediately inactivated by two kidney-specific kinin-inactivating enzymes (kininases), carboxypeptidase Y-like exopeptidase (CPY), and neutral endopeptidase (NEP). Our work demonstrated that ebelactone B and poststatin are selective inhibitors of these kininases. The reduced secretion of the urinary kallikrein is linked to the development of salt-sensitive hypertension, whereas potassium ions and ATP-sensitive potassium channel blockers ameliorate salt-sensitive hypertension by accelerating the release of renal kallikrein. On the other hand, ebelactone B and poststatin prolong the life of kinins in the CD after excess salt intake, thereby leading to the augmentation of natriuresis and diuresis, and the ensuing suppression of salt-sensitive hypertension. In conclusion, accelerators of the renal kallikrein release and selective renal kininase inhibitors are both novel types of antihypertensive agents that may be useful for treatment of salt-sensitive hypertension.
authors.forename: Makoto
authors.initials: M
authors.lastname: Katori
authors.forename: Masataka
authors.initials: M
authors.lastname: Majima
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D006801:Humans; D006973:Hypertension / Q000188:drug therapy* / Q000201:enzymology / Q000209:etiology / Q000235:genetics / Q000503:physiopathology; D007668:Kidney / Q000187:drug effects* / Q000201:enzymology / Q000503:physiopathology; D007705:Kinins / Q000235:genetics / Q000378:metabolism*; D007783:Lactones / Q000627:therapeutic use; D009842:Oligopeptides / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects; D017673:Sodium Chloride, Dietary / Q000009:adverse effects*; D020840:Tissue Kallikreins / Q000235:genetics / Q000378:metabolism*
chemical_list: D000959:Antihypertensive Agents; D004791:Enzyme Inhibitors; D007705:Kinins; D007783:Lactones; D009842:Oligopeptides; D017673:Sodium Chloride, Dietary; C071400:poststatin; C030795:ebelactone B; D020840:Tissue Kallikreins