Abstract
Acute intra-renal infusion of bradykinin increases diuresis and natriuresis via inhibition of vasopressin activity. However, the consequences of chronically increased bradykinin in the kidneys have not yet been studied. A new transgenic animal model producing an excess of bradykinin by proximal tubular cells (KapBK rats) was generated and submitted to different salt containing diets to analyze changes in blood pressure and other cardiovascular parameters, urine excretion, and composition, as well as levels and expression of renin-angiotensin system components. Despite that KapBK rats excrete more urine and sodium, they have similar blood pressure as controls with the exception of a small increase in systolic blood pressure (SBP). However, they present decreased renal artery blood flow, increased intrarenal expression of angiotensinogen, and decreased mRNA expression of vasopressin V1A receptor (AVPR1A), suggesting a mechanism for the previously described reduction of renal vasopressin sensitivity by bradykinin. Additionally, reduced heart rate variability (HRV), increased cardiac output and frequency, and the development of cardiac hypertrophy are the main chronic effects observed in the cardiovascular system. In conclusion: (1) the transgenic KapBK rat is a useful model for studying chronic effects of bradykinin in kidney; (2) increased renal bradykinin causes changes in renin angiotensin system regulation; (3) decreased renal vasopressin sensitivity in KapBK rats is related to decreased V1A receptor expression; (4) although increased renal levels of bradykinin causes no changes in mean arterial pressure (MAP), it causes reduction in HRV, augmentation in cardiac frequency and output and consequently cardiac hypertrophy in rats after 6 months of age.
Highlights
The kallikrein-kinin system (KKS) is present throughout the body
Studies in dogs showed that infusion of BK in the kidneys increases urinary volume (UV) and sodium excretion (UNaV), without changing glomerular filtration rate (GFR) and these effects are blocked by pretreatment with the B2 receptor (B2R) antagonist HOE-140 [17]
The DNA construct coding for an engineered fusion protein controlled by the kidney androgen-regulated protein (Kap) promoter was inserted into the genome of Sprague-Dawley rats to elicit BK overproduction in the proximal convoluted tubule
Summary
The kallikrein-kinin system (KKS) is present throughout the body. Bradykinin (BK) is its main effective peptide and has two sources: it is released from circulating high molecular weight kininogen by the action of plasma kallikrein; or from low molecular weight kininogen by the action of tissue kallikrein [1]. Usual approaches to test intrarenal effects of BK are the renal artery infusion of BK or antagonists of its receptors [8,9,10], intrarenal tissue BK infusion [11], the use of knockout animals [12, 13], or in vitro studies [14, 15]. More recent studies have shown that infusion of BK into the kidneys causes increased urinary volume and increased sodium secretion, with no change in BP [16]. Studies in dogs showed that infusion of BK in the kidneys increases urinary volume (UV) and sodium excretion (UNaV), without changing glomerular filtration rate (GFR) and these effects are blocked by pretreatment with the B2R antagonist HOE-140 [17]. Schuster et al has shown that lysylBK inhibits the effect of vasopressin with respect to hydraulic conductivity (Lp) in the rabbit cortical collecting tubule perfused in vitro [18]. Hebert et al concluded that this effect is transmitted via B2R and is independent of calcium signaling in the cortical collecting ducts
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