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Kallikrein-kinin system (KKS) is a vasodilator peptide system. Kinins, the active peptides, are produced by tissue kallikrein (TK), and act via their two receptors, B1 and B2. KKS was involved in the pathophysiological process leading to type 2 diabetes. Its role is well established in the protection of cardiovascular and renal complications of diabetes. We studied the role of SKK in the development of metabolic abnormalities associated with obesity using TK deficient mice in two models of obesity (Ob/Ob and high fat diet). We did not observed any effect of TK deficiency on metabolic parameters in these two models. In humans, we studied the effect of a polymorphism of TK in a population-based cohort of 4843 subjects followed for 9 years. We did not observe any effect of a partial deficiency in TK on the occurrence of metabolic disorders. Next, we studied the effect of specific agonists of B1 and B2 receptors in cardiac ischemia reperfusion injury. In non-diabetic mice, the B2 agonist reduces infarct size. Agonist B1 has no effect. In diabetic mice, B2 agonist had no effect. In contrast, B1 agonist reduces infarct size. Overexpression of B1R is observed in the diabetic heart. Our work clarifies the role of SKK in the development of diabetes and its cardiac complications. Agonists of kinins receptors could be a new therapeutic approach in the management of acute coronary syndrome., Le système kallicréine-kinines (SKK) est un système peptidique vasodilatateur. Les métabolites actifs du système, les kinines, sont produites par la kallicréine tissulaire (TK), et agissent via leurs deux récepteurs, B2 et B1. Le SKK a été impliqué dans les processus physiopathologiques conduisant au diabète de type 2. Son rôle est bien établi dans la protection des complications cardiovasculaires et rénales du diabète. Nous avons étudié le rôle du SKK dans le développement des anomalies métaboliques liées à l'obésité en utilisant des souris déficientes en TK dans deux modèles d'obésité (mutation ob/ob et régime gras). Nous n'avons pas mis en évidence d'effet de la déficience en TK sur les anomalies glucidiques dans ces deux modèles. Chez l'homme, nous avons étudié l'effet d'un polymorphisme génétique de la TK dans une cohorte de 4843 sujets de la population générale suivi pendant 9 ans. Nous n'avons pas observé d'effet d'un déficit partiel en activité TK sur l'apparition des troubles glucidiques.Ensuite, nous avons étudié l'effet de la stimulation du SKK par des agonistes spécifiques de chaque récepteur lors d'une ischémie reperfusion cardiaque. Chez les souris non diabétiques, l'agoniste B2 réduit la taille de l'infarctus. L'agoniste B1 n'a pas d'effet. Chez les souris diabétiques, l'agoniste B2 n'a pas d'effet. En revanche, l'agoniste B1 diminue la taille de l'infarctus. On observe une induction de la synthèse du B1R dans le c¿ur diabétique.Nos travaux clarifient le rôle du SKK dans le développement du diabète et de ses complications cardiaques. L'effet des agonistes ouvre une nouvelle piste thérapeutique dans la prise en charge des du syndrome coronarien aigu.

The antihypertensive effect of renal denervation in hypertensive patients is partially explained by increased tubular natriuresis. To study the possible contribution of the kallikrein-kinin system (KKS) to this natriuretic effect in rats, we measured kallikrein activity (KA) and bradykinin concentrations (BK) in plasma and tissues.To measure KA, we adapted and validated an enzymatic assay that cleaves para-nitroaniline (pNA) from the tripeptide H-D-Pro-Phe-Arg-pNA. The coefficients of variation (CV) within- and between-assays were less than 8% for plasma and tissue KA (plasma n=6 and 13; tissue n=4). Linear results for serially diluted samples confirmed the assay specificity. Tissue BK determinations were based on an established assay for plasma BK: tissue was homogenized and kinins extracted in ethanol, and BK was isolated by high-performance (HPLC) liquid chromatography and quantitated by radioimmunassay. Within- and between-assay CV for plasma BK were 18% (n=8 and n=35, respectively) and for BK in various tissues less than 16% (n=5-8).In male Wistar rats (n=3), plasma BK was 8.2 ± 6.6 fmol/mL (mean ± SD), and tissue BK (fmol/g) in 14 tested organs varied between brain (14 ± 3) and submaxillary gland (521 ± 315). Six days after left-sided unilateral renal denervation, left renal tissue BK (89 ± 9) was not different from right renal BK (75 ± 23). Similarly, KA was comparable in the two kidneys (left 18.0 ± 1.5, right 15.8 ± 1.4 μkat/g).Any possible effect of unilateral renal denervation on the kidney's KKS would have to be bilateral.

International audience; The incidence of chronic kidney disease leading to end-stage renal disease has significantly increased and may reach epidemic proportions over the next decade. Regardless of the initial insult, the progression of most forms of renal disease results in tubulo-interstitial fibrosis. This has been closely correlated to the future appearance of renal failure and has therefore been associated with poor long-term prognosis. New molecules and agents to limit the development of tubulo-interstitial fibrosis and slow down the progression towards end-stage renal disease are needed. In the past twenty years, many efforts have been made to understand the mechanisms of tubulo-intersititial fibrosis with the final goal to develop new therapeutic strategies. In this context, this review will focus on the mechanisms and factors involved in the development and the progression of renal fibrosis and will discuss the new promising therapeutic strategies in animal and humans.

Angiotensin converting enzyme inhibitors are a class of drugs successfully used in the treatment of cardiovascular diseases. Despite their effectiveness, treatment with these drugs is characterized by chronic and acute side effects with variable expression depending on the clinical context. Angioedema occurs in patients with hypertension or heart failure. Anaphylactoid reaction is also reported in hemodialysis patients and severe hypotensive reaction in patients receiving transfused blood products and plasmapheresis. In this paper, we describe the role of kinins and metallopeptidases in the pathophysiology of these acute side effects. We also propose different experimental and clinical evidences which plead for an ecogenetic nature of these rare but life-threatening events.

Coagulation, fibrinolysis and kinin-kallicrein system disorders could explain chronic subdural hematoma pathophysiology. The marked decrease in antithrombin III in the hematoma suggest that the decreased levels of clotting factors were caused by excessive coagulation resulting in clotting factors consumption. The decrease in alpha 2-antiplasmin with the increase of fibrin degradation products suggest that hyperfibrinolytic activity of the subdural hematoma. Coagulation and fibrinolysis disorders could explain repetitive hemorrhages from the outer membrane, which cause progressive enlargement of the hematoma. Kinin-kallicrein system disorders raise the hemorrhage by its action on the outer membrane. Nowadays, the earliest osmotic theory should reasonably be abandoned.

The purpose of the present review dedicated to the kallikrein-kininogen-kinin system is to highlight the pathophysiological role of this complex system in kidney diseased patients. We will focus mainly on the nature of bradykinin and its active metabolite, des-Arg9-bradykinin. After the description of their properties, their metabolism and their receptors, we will show the recent evidence about the renal kallikrein-kinine system and its autocrin/paracrin role. This will allow to the nephrologist a better understanding of the role of these vasoactive peptides not only in the beneficial aspects, but also in the acute side-effects, of angiotensin-converting enzyme inhibitors.

Spectral analysis was recently chosen to characterize the fast oscillations depending on the autonomic nervous system. Humoral stimuli could impinge on low frequency (LF) domain of blood pressure (BP) since the time lag to humoral systems activation is larger. This study was designed to analyse LF components of short-term variability of BP of conscious rats in conditions where humoral systems were activated. We studied rats with two-kidney Goldblatt hypertension in which the BP level was dependent upon the renin-angiotensin and kallikrein-kinin systems. Spectral powers of the systolic and diastolic BP and heart rate (HR) were computed in the high (respiratory, HF), mid (0.2-0.6 Hz, MF) and low (0.02-0.2 Hz, LF) frequency bands, as detected by the Fast Fourier Transform technique on consecutive 102-s stationary periods. Renal hypertension by a two-kidney one clip procedure was associated with a marked rise in SBP (+47 mmHg) and no significant change in HR. Renal hypertension selectively increased the LF component of SBP (+86%) when hypertensive rats were compared to sham operated animals. First, administration of losartan, a selective nonpeptide angiotensin II receptor antagonist, to sham rats resulted in a moderate SBP decrease, a significant tachycardia (+47 batt/min) with no change in BP and HR spectra profiles. Losartan determined in the hypertensive group a marked fall in SBP (-25 mmHg) with a significant tachycardia (+50 batt/min). Interestingly, losartan reduced the LF component of SBP (-26%). In a second series of normotensive and hypertensive rats, Hoe 140, a bradykinin B-2 receptor antagonist, did not affect the BP and HR levels of the two groups of rats. Hoe 140 decreased the LF component of SBP variability (-28%). Losartan, added after Hoe 140, decreased the BP (-17 mmHg) in association with a tachycardia (+59 batt/min) and induced a supplementary decrease of the LF component of SBP variability (-60%) in hypertensive rats. After the combined blockade, the LF component of SBP of the hypertensive rats was equivalent to that of the sham rats. Thus, an increase in the LF component of BP variability was observed in a model of hypertension where the BP is dependent upon humoral factors. The contribution of the renin-angiotensin and kallikrein-kinin systems in the slow fluctuations of BP was demonstrated using two specific antagonists losartan and Hoe 140.

Coagulation and fibrinolysis are not activated in an isolated system but it involves numerous interrelations with the kininogen-kinin pathway and the complement. In severe sepsis, substances released by microorganisms, notably lipopolysaccharides, can activate the contact system, and particularly in such circumstances, contact activation probably plays a role in the occurrence of haemodynamic changes and consumption coagulopathy. Evidence of kininogen-kinin pathway activation as assessed by biological investigations in patients with severe sepsis, could lead to the therapeutical use of natural or synthetic protease inhibitors.