Previous proteomic and transcriptional analyses of multiple sclerosis lesions1, 2, 3 revealed modulation of the renin-angiotensin and the opposing kallikrein-kinin pathways. Here we identify kinin receptor B1 (Bdkrb1) as a specific modulator of immune cell entry into the central nervous system (CNS). We demonstrate that the Bdkrb1 agonist R838 (Sar-[d-Phe]des-Arg9-bradykinin) markedly decreases the clinical symptoms of experimental autoimmune encephalomyelitis (EAE) in SJL mice4, 5, 6, whereas the Bdkrb1 antagonist R715 (Ac-Lys-[d-βNal7, Ile8]des-Arg9-bradykinin) resulted in earlier onset and greater severity of the disease. Bdkrb1-deficient (Bdkrb1−/−) C57BL/6 mice7 immunized with a myelin oligodendrocyte glycoprotein fragment, MOG35–55, showed more severe disease with enhanced CNS-immune cell infiltration. The same held true for mixed bone marrow–chimeric mice reconstituted with Bdkrb1−/− T lymphocytes, which showed enhanced T helper type 17 (TH17) cell invasion into the CNS. Pharmacological modulation of Bdkrb1 revealed that in vitro migration of human TH17 lymphocytes across blood-brain barrier endothelium is regulated by this receptor. Taken together, these results suggest that the kallikrein-kinin system is involved in the regulation of CNS inflammation, limiting encephalitogenic T lymphocyte infiltration into the CNS, and provide evidence that Bdkrb1 could be a new target for the treatment of chronic inflammatory diseases such as multiple sclerosis.

Background:Neurolysin is known to cleave several bioactive peptides in vitro. Results: Neurolysin knock-out mice showed increased glucose tolerance, insulin sensitivity, and gluconeogenesis, which likely relates to increased expression of both specific liver mRNAs and intracellular peptides. Conclusion: Neurolysin plays a role in energy metabolism. Significance: Neurolysin could be used as a therapeutic target to counteract insulin resistance.The oligopeptidase neurolysin (EC 3.4.24.16; Nln) was first identified in rat brain synaptic membranes and shown to ubiquitously participate in the catabolism of bioactive peptides such as neurotensin and bradykinin. Recently, it was suggested that Nln reduction could improve insulin sensitivity. Here, we have shown that Nln KO mice have increased glucose tolerance, insulin sensitivity, and gluconeogenesis. KO mice have increased liver mRNA for several genes related to gluconeogenesis. Isotopic label semiquantitative peptidomic analysis suggests an increase in specific intracellular peptides in gastrocnemius and epididymal adipose tissue, which likely is involved with the increased glucose tolerance and insulin sensitivity in the KO mice. These results suggest the exciting new possibility that Nln is a key enzyme for energy metabolism and could be a novel therapeutic target to improve glucose uptake and insulin sensitivity.

Rationale: Positive outward remodeling of pre-existing collateral arteries into functional conductance arteries, arteriogenesis, is a major endogenous rescue mechanism to prevent cardiovascular ischemia. Collateral arterial growth is accompanied by expression of kinin precursor. However, the role of kinin signaling via the kinin receptors (B1R and B2R) in arteriogenesis is unclear.Objective: The purpose of this study was to elucidate the functional role and mechanism of bradykinin receptor signaling in arteriogenesis. Key Words: bone marrow transplantation Ⅲ bradykinin receptors Ⅲ collateral growth Ⅲ leukocytes A rteriogenesis is the process that involves the flow-induced outward remodeling of preexisting collateral arterial pathways into functional conductance arteries (biological bypass). As a result of the arteriogenesis process, blood perfusion to the compromised region is restored; 1 therefore, it is regarded as a clinically highly relevant target. It is established that arteriogenesis is triggered by changes in local hemodynamic conditions and subsequent activation of inflammatory pathways. We previously showed that expression of kininogen, a precursor of the vasoactive kinin peptides, was selectively expressed in growing collaterals of the rat brain. 2 Here we investigated the role of kinin signaling in bradykinin receptor-deficient mice for collateral growth and evaluated whether stimulation with bradykinin receptor antagonists/agonists may modulate arteriogenesis in mice and rats. Our data suggest that the kinin-receptor signaling pathway may act as a molecular link between changes in hemodynamic forces (artery occlusion) and the activation of inflammatory pathways, including attraction of bone marrow Original Methods and Results:

Background: Angiotensin II, the renin-angiotensin system effector peptide, interacts with a recently discovered binding site that is distinctly different from its classic receptors. Results: A radioiodinated angiotensin II photoprobe bound to a ϳ75-kDa membrane protein, enabling its isolation and identification. Conclusion: Membrane-bound metalloendopeptidase neurolysin (EC 3.4.24.16) is the novel angiotensin-binding protein.Significance: This metalloendopeptidase may be a crucial component of the renin-angiotensin system.