Abstract
The kallikrein-kinin system (KKS) consists of two major cascades in mammals: “plasma KKS” consisting of high molecular-weight (HMW) kininogen (KNG), plasma kallikrein (KLKB1), and bradykinin (BK); and “tissue KKS” consisting of low molecular-weight (LMW) KNG, tissue kallikreins (KLKs), and [Lys0]-BK. Some components of the KKS have been identified in the fishes, but systematic analyses have not been performed, thus this study aims to define the KKS components in teleosts and pave a way for future physiological and evolutionary studies. Through a combination of genomics, molecular, and biochemical methods, we showed that the entire plasma KKS cascade is absent in teleosts. Instead of two KNGs as found in mammals, a single molecular weight KNG was found in various teleosts, which is homologous to the mammalian LMW KNG. Results of molecular phylogenetic and synteny analyses indicated that the all current teleost genomes lack KLKB1, and its unique protein structure, four apple domains and one trypsin domain, could not be identified in any genome or nucleotide databases. We identified some KLK-like proteins in teleost genomes by synteny and conserved domain analyses, which could be the orthologs of tetrapod KLKs. A radioimmunoassay system was established to measure the teleost BK and we found that [Arg0]-BK is the major circulating form instead of BK, which supports that the teleost KKS is similar to the mammalian tissue KKS. Coincidently, coelacanths are the earliest vertebrate that possess both HMW KNG and KLKB1, which implies that the plasma KKS could have evolved in the early lobe-finned fish and descended to the tetrapod lineage. The co-evolution of HMW KNG and KLKB1 in lobe-finned fish and early tetrapods may mark the emergence of the plasma KKS and a contact activation system in blood coagulation, while teleosts may have retained a single KKS cascade.
Highlights
The kallikrein-kinin system (KKS) is a conserved set of proteins in vertebrates, which is involved in cardiovascular regulation, inflammation, immune function, pain perception, kidney function, and drinking [1,2]
Only a single displaceable band was identified in each plasma sample, which suggested that teleosts possess KNG of a single molecular weight instead of high molecular-weight (HMW) and low molecular-weight (LMW) KNGs in mammals
By comparing the observed and predicted molecular weights of KNGs in various teleost species, the percentage glycosylation ranges from 23 - 30%, which is comparable to those of LMW KNGs in mammals (Table 1)
Summary
The kallikrein-kinin system (KKS) is a conserved set of proteins in vertebrates, which is involved in cardiovascular regulation, inflammation, immune function, pain perception, kidney function, and drinking [1,2]. The functions of kinins are often antagonistic to those of the renin-angiotensin system (RAS) and the two systems often crosstalk at cascade, receptor, and signaling levels [3,4,5]. A plasma KKS and a tissue KKS, are the major pathways for the formation of kinins in mammals [6]. In the plasma KKS, high molecular-weight (HMW) kininogen (KNG) is cleaved by plasma kallikrein (KLKB1), to form a nonapeptide known as bradykinin (BK). In the tissue KKS, low molecular-weight (LMW) KNG is cleaved by tissue kallikreins (KLKs) to form a decapeptide called [Lys0]-BK or kallidin (see Figure 1 for summary). The HMW and LMW KNGs are products of alternative splicing from the same kng, with the same N-
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