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Genetic Basis of Blood Pressure and Hypertension
Published in Giuseppe Mancia, Guido Grassi, Konstantinos P. Tsioufis, Anna F. Dominiczak, Enrico Agabiti Rosei, Manual of Hypertension of the European Society of Hypertension, 2019
Sandosh Padmanabhan, Alisha Aman, Anna F. Dominiczak
There are multiple lines of evidence supporting the link between the kidney, sodium and HTN. Guyton’s ‘pressure-natriuresis’ model posits that arterial pressure increases in response to a high NaCl intake, in turn leading to increases in urinary sodium excretion to maintain sodium balance (30–32). Renal transplant studies in rats and in humans have shown that the HTN status of the donor has a major impact on long-term BP in the recipients (50,51). Finally, Mendelian forms of syndromic hypotension and HTN (39) have all been linked to mutations in genes whose encoded proteins regulate salt—water balance in the kidney, supporting the primacy of the kidneys in BP regulation. The RAAS contributes to the regulation of BP not only through the salt-retaining properties of the mineralocorticoid hormone aldosterone (CYP11B2) but also through the vasoconstrictor properties of angiotensin II. RAAS involves the renin (REN) acting on angiotensinogen (AGT), to form an inactive decapeptide, angiotensin I, which is converted by an angiotensin-converting enzyme (ACE) to angiotensin II which binds to angiotensin II receptors (AGTR1). ACE also cleaves and inactivates a number of other peptides including the vasodilator bradykinin, which is cleaved from kininogen (KNG1) by kallikrein (KLK1) (Figure 7.1).
Lanadelumab for the treatment of hereditary angioedema
Published in Expert Opinion on Biological Therapy, 2019
Therefore, Lanadelumab has no inhibiting action on other serin-proteases, like Factor XIa and the zymogen prekallikrein, the latter feature being useful to achieve efficacy with lower amounts of drug while permitting basal plasma kallikrein activity to be maintained. This important characteristic of the drug was shown starting from preclinical studies whose results highlighted that at a 1 μM concentration lanadelumab had no inhibiting effect on other serine proteases (even on those with a remarkable homology to plasma kallikrein as FXIa) or on tissue kallikrein 1 (KLK1) [41]. To this regard, it is currently recognized that KLK1 exerts important protective action on cardiovascular and renal functions [45].
Kallikrein-related peptidases represent attractive therapeutic targets for ovarian cancer
Published in Expert Opinion on Therapeutic Targets, 2018
Daniela Loessner, Peter Goettig, Sarah Preis, Johanna Felber, Holger Bronger, Judith A. Clements, Julia Dorn, Viktor Magdolen
In normal physiology [13], tissue expression of KLKs is observed throughout the body (Figure 2). KLK1, KLK5–8 and KLK10–13 are moderately or highly expressed in several different tissues, whereas KLK2, KLK3 and – to a lesser extent – KLK4 are mainly expressed in the prostate. KLK9, KLK14 and KLK15 are rather weakly expressed in adults. In some cases, several KLKs seem to form a tissue-specific proteolytic network to fulfill physiologically important processes.
Serine protease inhibitors to treat inflammation: a patent review (2011-2016)
Published in Expert Opinion on Therapeutic Patents, 2018
Feryel Soualmia, Chahrazade El Amri
Among the relatively new serine proteases, ‘tissue’ kallikreins or kallikrein-related peptidases – as distinct from ‘plasma’ kallikrein – form a family of proteases present in at least six orders of mammals. In humans, tissue kallikreins (KLKs, hKLKs, or hKs for human kallikreins) are coded by 15 structurally similar genes (KLK) which co-locate in tandem on chromosome 19q13.4, thus representing the largest cluster of contiguous protease genes in the human genome [73–75]. They include human kallikrein KLK1 and the other 14 kallikrein-related peptidases (KLK2–KLK15). The first member of this family, KLK1, was characterized in the pancreas almost a century ago and named ‘kallikrein’ in reference to this organ (καλλικρεας in Greek). With KLK3 or ‘PSA’ (prostate-specific antigen), discovered in the 1960s, and KLK2, whose gene was isolated in the 1980s, KLK1 belongs to the subfamily of ‘classical kallikreins.’ These 3 proteases are more closely related to each other than the 12 ‘new kallikreins’ KLK4-15 whose progressive assignment to the KLKs family only began in the late 1990s. Thus, the KLKs family was best known for the role of KLK1 in the kallikrein–kinin system or for the use of KLK3 or ‘PSA’ (and, to a lesser extent, KLK2) as a biomarker in screening for prostate cancer. However, during the last decade, great progress has been made in understanding the cellular and tissue localization and in vivo logical physio(patho) regulation of most KLKs [76,77]. Significant new functional concepts have therefore emerged following the development of animal models with selectively modified kallikreins (or endogenous inhibitors) and the identification of individuals with natural KLKs deficiencies. Kallikreins and kallikrein-related peptidases are now well known for their involvement in renal function, desquamation, dental enamel formation, reproduction, synaptic plasticity, and cerebral function [4,78]. At the same time, the importance of fine regulation of their in vivo activity has become evident as with all proteases. Their activity is thus modulated by mechanisms and regulatory factors similar to those of serine proteases such as their cascade activations, their microenvironment, and their endogenous inhibitors. Thus, the loss of tissue-specific regulation of kallikreins has been linked to various conditions including respiratory diseases, neurodegeneration, anxiety, schizophrenia, skin barrier dysfunction, inflammation, and cancer. A recent study from Lizama et al. has experimentally confirmed for the first time the presence of kallikrein-related peptidases in the human neutrophil [79]. It has been particularly shown that a kinin B1 receptor agonist induces the secretion of KLK1, KLK6, KLK10, KLK13, and kallikrein 14 (KLK14) with similar amounts as those induced by the well-known chemotactic peptide (f-Met–Leu–Phe). Thus, secretion of KLKs to the inflammatory milieu, induced either by kinins or other pro-inflammatory mediators, leads to human neutrophils with an enhanced enzymatic capacity that may be relevant in certain human disorders.