icatibant and Kidney-Diseases

The kallikrein-kinin system is an endogenous metabolic cascade, triggering of which results in the release of vasoactive kinins (bradykinin-related peptides). This complex system includes the precursors of kinins known as kininogens and mainly tissue and plasma kallikreins. The pharmacologically active kinins, which are often considered as either proinflammatory or cardioprotective, are implicated in many physiological and pathological processes. The interest of the various components of this multi-protein system is explained in part by the multiplicity of its pharmacological activities, mediated not only by kinins and their receptors, but also by their precursors and their activators and the metallopeptidases and the antiproteases that limit their activities. The regulation of this system by serpins and the wide distribution of the different constituents add to the complexity of this system, as well as its multiple relationships with other important metabolic pathways such as the renin-angiotensin, coagulation, or complement pathways. The purpose of this review is to summarize the main properties of this kallikrein-kinin system and to address the multiple pharmacological interventions that modulate the functions of this system, restraining its proinflammatory effects or potentiating its cardiovascular properties.

Topics: Angioedema; Angiotensin-Converting Enzyme Inhibitors; Animals; Aprotinin; Bradykinin; Bradykinin B2 Receptor Antagonists; Cardiovascular Diseases; Complement C1 Inactivator Proteins; Complement C1 Inhibitor Protein; Humans; Inflammation; Kallikrein-Kinin System; Kallikreins; Kidney Diseases; Kinins; Neprilysin; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Pyridines; Randomized Controlled Trials as Topic; Receptor, Bradykinin B1; Receptor, Bradykinin B2; Serpins; Thiazepines

The albumin overload model induces proteinuria and tubulointersitial damage, followed by hypertension when rats are exposed to a hypersodic diet. To understand the effect of kinin system stimulation on salt-sensitive hypertension and to explore its potential renoprotective effects, the model was induced in Sprague-Dawley rats that had previously received a high-potassium diet to enhance activity of the kinin pathway, followed with/without administration of icatibant to block the kinin B₂ receptor (B₂R). A disease control group received albumin but not potassium or icatibant, and all groups were exposed to a hypersodic diet to induce salt-sensitive hypertension. Potassium treatment increased the synthesis and excretion of tissue kallikrein (Klk1/rKLK1) accompanied by a significant reduction in blood pressure and renal fibrosis and with downregulation of renal transforming growth factor-β (TGF-β) mRNA and protein compared with rats that did not receive potassium. Participation of the B₂R was evidenced by the fact that all beneficial effects were lost in the presence of the B₂R antagonist. In vitro experiments using the HK-2 proximal tubule cell line showed that treatment of tubular cells with 10 nM bradykinin reduced the epithelial-mesenchymal transdifferentiation and albumin-induced production of TGF-β, and the effects produced by bradykinin were prevented by pretreatment with the B₂R antagonist. These experiments support not only the pathogenic role of the kinin pathway in salt sensitivity but also sustain its role as a renoprotective, antifibrotic paracrine system that modulates renal levels of TGF-β.

Topics: Animals; Bradykinin; Bradykinin B2 Receptor Antagonists; Cell Line; Female; Fibrosis; Humans; Hypertension; Kidney Diseases; Kidney Tubules; Kinins; Metabolic Networks and Pathways; Potassium, Dietary; Proteinuria; Rats; Rats, Sprague-Dawley; Serum Albumin, Bovine; Sodium Chloride, Dietary; Tissue Kallikreins; Transforming Growth Factor beta

1. We compared the effects of the angiotensin converting enzyme (ACE) inhibitor enalapril and the angiotensin AT(1) receptor antagonist valsartan in cyclosporine A (CsA)-induced hypertension and nephrotoxicity in spontaneously hypertensive rats (SHR). 2. SHR (8 - 9 weeks old) on high-sodium diet were given CsA (5 mg kg(-1)d (-1) s.c. ) for 6 weeks. The rats were treated concomitantly either with enalapril (30 mg kg(-1)d (-1) p.o.) or valsartan (3 or 30 mg kg(-1) d (-1) p.o.). To evaluate the role of bradykinin in the action of enalapril, some rats received a bradykinin B(2) receptor antagonist icatibant (HOE 140, 500 microg kg(-1) d (-1) s.c.) during the last 2 weeks of enalapril treatment. 3. Blood pressure was recorded every second week by tail cuff method. Renal function was measured by serum creatinine, creatinine clearance and urinary excretion of proteins at the end of the experiment. The activity of the renal kallikrein-kinin system was estimated by urinary kallikrein excretion. 4. CsA caused hypertension, impaired renal function and induced morphological nephrotoxicity with glomerular damage and interstitial fibrosis. Enalapril and the lower dose of valsartan attenuated the CsA-induced hypertension to the same extent, while the higher dose of valsartan totally abolished it. Icatibant did not reduce the antihypertensive effect of enalapril. Urinary kallikrein excretion was similar in all groups. 5. Enalapril and valsartan equally prevented the CsA-induced deterioration of kidney function and morphology. 6. The renin-angiotensin but not the kallikrein-kinin system plays a crucial role in CsA-toxicity during high intake of sodium in SHR.

Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Blood Pressure; Body Weight; Bradykinin; Bradykinin Receptor Antagonists; Cyclosporine; Dose-Response Relationship, Drug; Drinking; Eating; Electrolytes; Enalapril; Heart Rate; Hypertension; Hypertrophy, Left Ventricular; Kallikreins; Kidney; Kidney Diseases; Male; Rats; Rats, Inbred SHR; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptor, Bradykinin B2; Renin; Sodium, Dietary; Tetrazoles; Urination; Valine; Valsartan

1. We assessed the potential of the kallikrein-kinin system in mediating the cardioprotective and renoprotective effects of an angiotensin-converting enzyme inhibitor (ACEI), cilazapril (CIL) in rats with renal ablation. 2. Eight week old spontaneously hypertensive rats (SHR) were subjected to 5/6 nephrectomy. One week after the operation, the rats were divided into 5 groups: (i) vehicle; (ii) CIL 1 mg/kg per day per os (p.o.); (iii) Hoe140 (HOE) 70 mu g/kg per day given intraperitoneally (i.p.); (iv) CIL 1 mg/kg per day p.o. plus HOE 7 mu g/kg per day i.p.; (v) CIL 1 mg/kg per day p.o. plus HOE 70 mu g/kg per day i.p. The treatment lasted for 4 weeks. 3. CIL alone significantly reduced systolic blood pressure, urinary protein excretion, heart weight and serum creatinine level. HOE alone did not induce any significant changes in these parameters. CIL in combination with HOE (7 or 70 mu g/kg per day) did not induce any changes in these parameters, in addition to those associated with the effects of CIL alone. 4. These results indicate that the kallikrein-kinin system might not play a major role in the cardioprotective and renoprotective effects of ACE inhibitors in the rat remnant kidney model of chronic renal failure.

Topics: Adrenergic beta-Antagonists; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Bradykinin; Cilazapril; Heart Diseases; Kidney; Kidney Diseases; Kidney Failure, Chronic; Kidney Function Tests; Kinins; Nephrectomy; Organ Size; Rats; Rats, Inbred SHR