Extracellular aspartic protease SAP2 of Candida albicans yeast cleaves human kininogens and releases proinflammatory peptides, Met-Lys-bradykinin and des-Arg⁹-Met-Lys-bradykinin

Abstract

Bradykinin-related peptides, universal mediators of infl ammation collectively referred to as the kinins, are often produced in excessive amounts during microbial infections. We have recently shown that the yeast Candida albicans , the major fungal pathogen to humans, can exploit two mechanisms to enhance kinin levels at the sites of candidial infection, one depending on adsorption and activation of the endogenous kinin-generating system of the host on the fungal cell wall and the other relying on cleavage of kinin precursors, the kininogens, by pathogen-secreted proteases. This work aimed at assigning this kininogenase activity to the major secreted aspartic protease of C. albicans (SAP2). The purifi ed SAP2 was shown to cleave human kininogens, preferably the low molecular mass form (LK) and optimally in an acidic environment (pH 3.5 -4.0), and to produce two kinins, Met-Lys-bradykinin and its derivative, [Hydroxyproline 3 ]-Met-Lys-bradykinin, both of which are capable of interacting with cellular bradykinin receptors of the B2 subtype. Additionally, albeit with a lower yield, des-Arg 9 -Met-Lysbradykinin, an effective agonist of B1-subtype receptors, was released. The pathophysiological potential of these kinins and des-Arg-kinin was also proven by presenting their ability to stimulate human promonocytic cells U937 to release proinfl ammatory interleukin 1 β (IL-1 β ) and IL-6.

A Role for Bradykinin Signaling in Chronic Vulvar Pain

“…Bradykinin-related peptides, or kinins, are involved in nearly all types of inflammation and are clearly linked to pain phenotypes 10 . During inflammation, BDKRB1 and BDKRB2 expression is elevated and the local concentrations of their kinin agonists increase, although the precise concentrations of bradykinin at specific sites within the human body are largely unknown 56 .…”

“…At the same time, kinins induce the production of proinflammatory mediators, including nitric oxide, prostaglandins, and cytokines (e.g. IL-6) 10 , some of which are directly implicated in pain (e.g. PGE 2 and IL-6) 15–17, 19, 22, 23, 37, 45, 53, 61 .…”

“…We became interested in bradykinin because of its inflammatory and pain-inducing qualities 56 and the observation that Candida , which has been implicated in vulvar pain, may play a role in exacerbating the responses to bradykinin by generating locally elevated concentrations of bradykinin 9, 10, 35, 36, 39, 57 . Candida species produce serine aspartyl proteases that cleave human HMW kininogens, which is believed vital to pathogenesis and aids in tissue invasion by C. albicans 9, 10, 35, 39, 57 .…”

“…Candida species produce serine aspartyl proteases that cleave human HMW kininogens, which is believed vital to pathogenesis and aids in tissue invasion by C. albicans 9, 10, 35, 39, 57 . Therefore, we hypothesized that bradykinin may also play important roles in inflammation and pain within the vulvar vestibule.…”

Renin-angiotensin system (RAS) blockade attenuates growth and metastatic potential of renal cell carcinoma in mice

“…First, blockade of ACE increases the bradykinin concentration, and it is known that the kinin system influences carcinogenesis by stimulating the growth, survival, and migration of cancer cells by altering the permeability of the blood tumor barrier and through the release of proinflammatory cytokines [35][36][37][38]. In addition, Fernandes et al [39], using a murine model of Ehrlich tumor, found that bradykinin antagonists may inhibit tumor growth.…”