Renal Protective Role of Bradykinin B1 Receptor in Stroke-Prone Spontaneously Hypertensive Rats

Hagiwara, Makoto; Murakami, Hideyuki; Ura, Nobuyuki; Agata, Jun; Yoshida, Hiroyuki; Higashiura, Katsuhiro; Shimamoto, Kazuaki

doi:10.1291/hypres.27.399

Cited by 23 publications

(14 citation statements)

References 43 publications

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“…For example, B1R knock-out protects mice from lipopolysaccharide-induced hypotension, reduces pain in response to thermal or chemical stimuli as well as neuropathic pain, and reduces intestinal ischemia/reperfusion inflammation and lethality (62). However, B1R signaling also has numerous beneficial effects, such as promoting angiogenesis and neovascularization during wound healing (62)(63)(64), protecting kidneys from renal fibrosis and attenuating cardiac remodeling in stroke-prone spontaneously hypertensive rats (65,66), and reducing lethality in a porcine model of endotoxic shock (67). B1R stimulation also results in high output NO production in human endothelial cells (21,22) via activation of extracellular signal-regulated kinase and acute stimulation of inducible nitric-oxide synthase activity via phosphorylation of Ser 745 (23).…”

Section: Discussionmentioning

confidence: 99%

Carboxypeptidase M and Kinin B1 Receptors Interact to Facilitate Efficient B1 Signaling from B2 Agonists

Zhang

Tan

Zhang

et al. 2008

Journal of Biological Chemistry

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Kinin B1 receptor (B1R) expression is induced by injury or inflammatory mediators, and its signaling produces both beneficial and deleterious effects. Kinins cleaved from kininogen are agonists of the B2R and must be processed by a carboxypeptidase to generate B1R agonists des-Arg 9 -bradykinin or desArg 10 Carboxypeptidase M (CPM) 2 was discovered as a glycosylphosphatidylinositol (GPI)-anchored membrane protein with B-type carboxypeptidase activity (1-3) and is a member of the "regulatory" or carboxypeptidase N/E subfamily of metallocarboxypeptidases (4 -8) based on its cDNA sequence (9), genomic structure (10), and x-ray crystal structure (11). The overall structure of CPM is composed of a 295-residue N-terminal catalytic domain, followed by an 86-residue conical ␤-sandwich (transthyretin-like domain) and a unique 25-residue extension to which the GPI anchor is post-translationally attached (11).CPM cleaves only C-terminal Arg or Lys residues, and some of its endogenous substrates include bradykinin, anaphylatoxins C3a, C4a, and C5a, Arg-or Lys-enkephalins, epidermal growth factor, and hemoglobin (2, 7, 12, 13). CPM preferentially cleaves C-terminal Arg as exemplified by the kinetics with Arg 6 -Met 5 -enkephalin (K m ϭ 46 M, k cat ϭ 934 min Ϫ1 ) versus Lys 6 -Met 5 -enkephalin (K m ϭ 375 M, k cat ϭ 663 min Ϫ1 ) (2). Bradykinin exhibits the lowest K m (16 M) of any CPM substrate tested (2), a concentration that is still much higher than the typical physiological concentration of this peptide in the nanomolar range. However, peptidases in vivo typically work at substrate concentrations far below the K m as exemplified by angiotensin I-converting enzyme (ACE), which has the same relatively high K m (16 M) with angiotensin I (14), a major physiological substrate. The development of ACE inhibitors as effective agents for treating hypertension and cardiovascular diseases was based in large part on the critical role of this enzyme in converting angiotensin I to II in vivo (15).The kinin peptides bradykinin and kallidin (Lys-bradykinin) are generated by the proteolytic action of plasma or tissue kallikrein on high or low molecular weight kininogen (16,17). Removal of the C-terminal Arg from bradykinin or kallidin inactivates these peptides as agonists of the constitutively expressed B2 receptor (B2R) (16,17). However, this conversion is a required processing step to generate desArg 9 -bradykinin or des-Arg 10 -kallidin (16, 18), metabolites that have a variety of biological activities mediated by specific activation of a different B1 receptor (B1R) whose expression is induced by inflammatory mediators (19,20). Thus, CPM acts as a cell surface processing enzyme to generate des-Arg-kinin agonists for the B1R, and without this catalytic conversion, B1R signaling could not occur. This is of potential importance in inflammatory or pathological responses. For example, B1R activation stimulates extracellular signal-regulated kinase phosphorylation, prostaglandin production (20), and inducible nitric-oxide synthase-mediate...

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Section: Discussionmentioning

confidence: 99%

Carboxypeptidase M and Kinin B1 Receptors Interact to Facilitate Efficient B1 Signaling from B2 Agonists

Zhang

Tan

Zhang

et al. 2008

Journal of Biological Chemistry

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“…For example, B1R stimulation enhances inflammation and fibrosis in diabetic cardiomyopathy (66) and B1R knock-out protects mice from lipopolysaccharide-induced hypotension and reduces pain in response to thermal or chemical stimuli (67). Conversely, B1R activation is protective in renal ischemia/reperfusion injury (68), reduces renal fibrosis and cardiac remodeling (69,70), and promotes neovascularization and angiogenesis during wound healing (67,71). B1R signaling also contributes to the beneficial cardiovascular effects of ACE inhibitors and angiotensin type 1 receptor blockers (72,73).…”

Section: Discussionmentioning

confidence: 99%

Carboxypeptidase M Is a Positive Allosteric Modulator of the Kinin B1 Receptor

Zhang¹,

Tan

Skidgel

2013

Journal of Biological Chemistry

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Background: Carboxypeptidase M (CPM) generates agonist for the kinin B1 receptor (B1R). Results: CPM binds to B1R on the cell membrane and allosterically increases B1R agonist affinity. Conclusion: CPM is a positive allosteric modulator of the B1R, thereby increasing receptor signaling. Significance: Interfering with CPM binding to B1R could be a novel approach to inhibit deleterious effects of B1R signaling in inflammation.

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“…Un seul travail est en faveur d'un rôle néphroprotecteur du RB1, montrant que le blocage pharmacologique de ce récepteur aggrave la fibrose rénale [35]. Le RB1 peut aussi avoir des effets anti-proliféra-tifs car il réduit l'hyperplasie de la média lors de lésions de la carotide chez le rat [36].…”

Section: Et Le Récepteur B1 ?unclassified