RENAL KALLIKREIN-KININ SYSTEM DECREASES DISTAL TUBULE SODIUM TRANSPORT
The local hormone peptides kinins, such as bradykinin, are principal effectors of the kallikrein-kinin system (KKS). Bradykinin is produced from the inactive precursor molecule kininogen following cleavage by the serine protease kallikrein [8]. Bradykinin interacts with G-protein-coupled B1 and B2 receptors (B1R and B2R, respectively) to stimulate numerous intracellular signaling cascades [9,10]. The biological effects of bradykinin are mediated mainly through the B2R which are constitutively expressed in smooth muscles, neurons, vascular endothelium, and kidney epithelial cells [11]. KKS is envisioned as a natural counterbalance of the RAAS. At the whole body level, KKS possesses multiple beneficial actions which reduce excessive burden on the cardiovascular system in response to RAAS activation [12]. This includes vasodilation, reduction of oxidative stress, stimulation of NO production, and augmentation of urinary sodium excretion [12-14]. Importantly, dysfunction KKS components, including kininogen [15], kallikrein [16], and B2R [17,18], causes hypertension in animal genetic models when sodium intake is elevated. Low urinary kallikrein levels are consistently found in individuals with essential hypertension [19]. A polymorphism in the human B2R gene (+9,+9) is linked to an increased cardiovascular risk and higher systolic BP [20]. In contrast, transgenic mice and rats overexpressing either human kallikrein (KLK1) or B2R genes are permanently hypotensive [21,22]. Altogether, this strongly supports the concept that the functional status of KKS is a critical component of BP control.
In addition to the well-documented actions in controlling vascular tone, kinins are also important regulators of renal sodium handling [23,24]. Interstitial fluid bradykinin levels are reported to be in the 10-100 nM range in both cortex and medulla regions of the rat kidney [25]. These concentrations are considerably higher than those present in the bloodstream [26] and more than sufficient to effectively stimulate B2R [27,28]. In perfused rat kidneys, acute pharmacological inhibition of B2 receptors with HOE-140 (icatibant) decreased urinary Na+ excretion without altering glomerular filtration rate (GFR) or renal blood flow [24]. Importantly, high dietary sodium intake potentiates the natriuretic actions of renal KKS [29] and consistently augments urinary excretion of bradykinin and kallikrein [30]. This salt dependence indicates that the principal action site for the KKS in the renal tubule is likely restricted to the distal segments.
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The distal part of the renal nephron, which includes the connecting tubule (CNT) and the cortical collecting duct (CCD), is recognized as playing a critical role in the negative feedback pathway that fine-tunes renal sodium excretion to match dietary Na+ intake [31■]. Sodium reabsorption here is under fine control by the RAAS to maintain systemic fluid volume and set chronic BP. Activity of the apically localized epithelial Na+ channel (ENaC) determines the electrogenic Na+-reabsorption in the distal nephron [31■]. ENaC is uniquely positioned to respond to changes in systemic Na+ balance [32,33]. Both aldosterone [34] and Ang II [35] have stimulatory actions on ENaC that are essential to prevent renal sodium losses, particularly during volume contractions. The physiological importance of ENaC in the regulation of BP in humans is emphasized by the inheritable forms of hypertension (Liddle’s syndrome) resulting from gain-of-function mutations of the channel [36-41]. Loss-of-function mutations, in contrast, lead to salt wasting and low BP (pseudohypoaldosteronism type I) [39,40].
Although the RAAS-mediated endocrine control of ENaC activity provides a mechanistic explanation of augmented Na+ reabsorption in the distal nephron during dietary sodium restriction, the concept of ENaC inhibition during volume-expanded states is just beginning to emerge. Effective suppression of ENaC activity during high sodium intake is viewed as an important regulatory mechanism that allows avoiding excessive sodium retention and salt-sensitive hypertension. An inability to decrease ENaC activity contributes to the development of elevated BP in humans [42] and in many salt-sensitive hypertensive animal models, such as salt-sensitive Dahl rats [43,44]. Recent experimental evidence strongly suggest that KKS, and specifically bradykinin, is essential for the proper regulation of ENaC activity by dietary salt intake particularly during volume expanded states [45■■,46].
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