title: The kallikrein-kinin system.
abstract: Emerging evidence suggests a role of the kallikrein-kinin system (KKS) in the pathogenesis of diabetic nephropathy (DN). Tissue kallikrein 1 is a member of the tissue kallikrein family that is mainly responsible for the generation of kinins, and bradykinin (BK) is the principal kinin responsible for the biologic actions of the KKS that acts through the ubiquitous BK 2receptor (B2R) and the inducible B1R. In the kidney, all KKS components are expressed. In particular, kallikrein 1 that is traditionally thought to be solely confined to the distal nephron has recently been identified in the proximal tubule of the human diabetic kidney. Current evidence suggests conflicting roles of the KKS in DN. For a renoprotective role of the KKS, BK reduces mesangial cell proliferation under the diabetic milieu; Akita B2R-/- or STZ-induced KLK-/- mice (T1DM) have more severe albuminuria and glomerulosclerosis, while antagonizing the B2R with icatibant attenuates the antiproteinuric effect of ramiprilin db/db mice (T2DM). For a detrimental role of the KKS, BK upregulates tubular cell IL-6, CCL-2, and TGF-β expression via ERK1/2 activation; the B2R-/- status protects against the development of DN lesions in STZ-injected mice, while blocking B2R with icatibant alleviates biochemical and histologic injuries in uninephrectomized db/db mice. These opposite findings may arise from multiple factors and call for further evaluation to clarify the role of the KKS in DN and diabetic tubulopathy.
authors.forename: Sydney Cw
authors.initials: SC
authors.lastname: Tang
authors.forename: Joseph C K
authors.initials: JCK
authors.lastname: Leung
authors.forename: Kar Neng
authors.initials: KN
authors.lastname: Lai
mesh_terms: D000818:Animals; D003928:Diabetic Nephropathies / Q000209:etiology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology; D006801:Humans; D016234:Kallikrein-Kinin System / Q000502:physiology*; D007610:Kallikreins / Q000032:analysis; D007687:Kidney Tubules, Proximal / Q000378:metabolism; D018002:Receptors, Bradykinin / Q000502:physiology
chemical_list: D018002:Receptors, Bradykinin; D048049:Extracellular Signal-Regulated MAP Kinases; D007610:Kallikreins; C120801:kallikrein 4