Tissue kallikrein in cardiovascular, cerebrovascular and renal diseases and skin wound healing

Abstract

Tissue kallikrein (KLK1) processes low-molecular weight kininogen to produce vasoactive kinins, which exert biological functions via kinin receptor signaling. Using various delivery approaches, we have demonstrated that tissue kallikrein through kinin B2 receptor signaling exhibits a wide spectrum of beneficial effects by reducing cardiac and renal injuries, restenosis and ischemic stroke, and by promoting angiogenesis and skin wound healing, independent of blood pressure reduction. Protection by tissue kallikrein in oxidative organ damage is attributed to the inhibition of apoptosis, inflammation, hypertrophy and fibrosis. Tissue kallikrein also enhances neovascularization in ischemic heart and limb. Moreover, tissue kallikrein/kinin infusion not only prevents but also reverses kidney injury, inflammation and fibrosis in salt-induced hypertensive rats. Furthermore, there is a wide time window for kallikrein administration in protection against ischemic brain infarction, as delayed kallikrein infusion for 24 h after cerebral ischemia in rats is effective in reducing neurological deficits, infarct size, apoptosis and inflammation. Importantly, in the clinical setting, human tissue kallikrein has been proven to be effective in the treatment of patients with acute brain infarction when injected within 48 h after stroke onset. Finally, kallikrein promotes skin wound healing and keratinocyte migration by direct activation of protease-activated receptor 1.

Tissue kallikrein protects against ischemic stroke by suppressing TLR4/NF-κB and activating Nrf2 signaling pathway in rats

“…However, numerous other studies support the results of the present study, indicating that TK exerts a neuroprotective effect in ischemic injury (24,25,46,47). This type of protective effect may be associated with the following factors: i) The actions of TK can be mediated by kinin B 2 receptor activation without kinin formation (48); ii) kallikrein-induced anti-inflammation is dependent on kinin B 2 receptor activation and nitric oxide formation (24); iii) upregulation of endothelial nitric oxides resulted in dilation of cerebral arterial vessels, which is critical in maintaining the cerebral blood flow and conducive to the removal of inflammatory mediators (25); and iv) in the early period following cerebral I/R, kallikrein induced angiogenesis and improved the regional cerebral blood flow in the peri-infarction region, and further reduced the infarction volume and improved the neurological deficits (46).…”

Autoimmune Diabetes Is Suppressed by Treatment with Recombinant Human Tissue Kallikrein-1

“…The KKS exerts physiological effects through binding of kinin peptides to the bradykinin 1 and bradykinin 2 receptors [7], [8]. In addition to the blood pressure lowering effects to balance the renin-angiotensin system [9], the KKS is proposed to improve insulin sensitivity [10], [11].…”

Spectrum of large copy number variations in 26 diverse Indian populations: potential involvement in phenotypic diversity

“…these could lead to variability in phenotypes and disease susceptibility. Various studies have reported involvement of keratinization, cadherins and serine proteases (Chao et al 2010) in skin physiology. It is possible that CNVRs in these enriched processes might explain the observable wide spectrum of skin pigmentation across Indian populations.…”