Role of blood pressure in mediating the influence of salt intake on renin expression in the kidney

Abstract

The salt intake of an organism controls the number of renin-producing cells in the kidney by yet undefined mechanisms. This study aimed to assess a possible mediator role of preglomerular blood pressure in the control of renin expression by oral salt intake. We used wild-type (WT) mice and mice lacking angiotensin II type 1a receptors (AT 1aϪ/Ϫ) displaying an enhanced salt sensitivity to renin expression. In WT kidneys, we found renin-expressing cells at the ends of all afferent arterioles. A low-salt diet (0.02%) led to a moderate twofold increase in reninexpressing cells along afferent arterioles. In AT 1aϪ/Ϫ mice, lowering of salt content led to a 12-fold increase in renin expression. Here, the renin-expressing cells were distributed along the preglomerular vascular tree in a typical distal-to-proximal distribution gradient which was most prominent at high salt intake and was obliterated at low salt intake by the appearance of renin-expressing cells in proximal parts of the preglomerular vasculature. While lowering of salt intake produced only a small drop in blood pressure in WT mice, the marked reduction of systolic blood pressure in AT 1aϪ/Ϫ mice was accompanied by the disappearance of the distribution gradient from afferent arterioles to arcuate arteries. Unilateral renal artery stenosis in AT 1aϪ/Ϫ mice on a normal salt intake produced a similar distribution pattern of reninexpressing cells as did low salt intake. Conversely, increasing blood pressure by administration of the NOS inhibitor N-nitro-L-arginine methyl ester or of the adrenergic agonist phenylephrine in AT1aϪ/Ϫ mice kept on low salt intake produced a similar distribution pattern of renin-producing cells as did normal salt intake alone. These findings suggest that changes in preglomerular blood pressure may be an important mediator of the influence of salt intake on the number and distribution of renin-producing cells in the kidney. AT1a knockoutTHE MAINTENANCE OF SALT HOMEOSTASIS is a central function of the renin-angiotensin-system. A threat to salt balance leads to compensatory changes in renin expression in the kidney in a way that the number of renin-expressing cells increases during salt deficiency and decreases during salt overload (41). It is assumed that the salt-related changes in renin-expressing cells in the kidney are not caused by cell proliferation or apoptosis, but instead result from reversible phenotype changes of preglomerular smooth muscle cells into renin-producing cells and vice versa (34). The intracellular signaling pathways defining the specific phenotype of these cells are yet unknown. Furthermore, it is unclear by which mechanisms salt balance controls the number of renin-producing cells. It has been suggested that the effects of salt balance may affect renin expression in the preglomerular afferent arterioles by autacoids such as nitric oxide (NO) or prostaglandins (42) since salt intake has been shown to control the juxtaglomerular expression of cyclooxygenase-2 (COX-2) (17) and nitric oxide synthase-1 (NOS-1) (37...

Salt feedback on the renin-angiotensin-aldosterone system

“…During longer lasting reductions of salt intake, the number of reninproducing cells increases by a reversible transformation of preglomerular vascular smooth muscle cells into reninproducing cells (Fig. 2) [71,75]. This upstream recruitment of renin-producing cells in renal vessels also occurs under stimulation of the RAAS by a drop of renal perfusion pressure for instance due to a renal artery stenosis or application of ACE inhibitors (Fig.…”

“…This upstream recruitment of renin-producing cells in renal vessels also occurs under stimulation of the RAAS by a drop of renal perfusion pressure for instance due to a renal artery stenosis or application of ACE inhibitors (Fig. 2) [71,75,85,104]. In response to severe salt-related challenges of the renin system such as salt loosing nephropathies, mutations or genetic deletions of the RAAS Fig.…”

Connexin 40 is dispensable for vascular renin cell recruitment but is indispensable for vascular baroreceptor control of renin secretion

“…We speculate therefore that the disappearance of RSCs in the preglomerular vessels and their ectopic appearance in the renocortical interstitium as typically seen in adult mice with functional defects of Cx40 in RSCs are distinct processes. Since recruitment and existence of RSCs in the walls of preglomerular vessels are considered to be dependent on the intrarenal blood pressure [1,6,21], in the way that low pressure favors and high pressure suppresses mural renin expression, the long-lasting hypertension found in all animal models with defective Cx40 function may have prevented mural renin expression by short-term maneuvers of blood pressure lowering. In contrast to Cx40 −/− mice, AT 1A (Table 1).…”

“…There were several reasons to use AT 1A −/− mice for this study. Firstly, they show a prominent vascular recruitment of RSCs, which can be triggered by low-salt intake [21]. Secondly, they have an ineffective renin-angiotensin-aldosterone system (RAAS), which should counteract effects of renin hypersecretion on the RAAS seen in Cx40-defective mice [21,28,29].…”

Plasticity of renal endocrine function

“…Chronic challenges of the RAAS, such as reduced renal perfusion pressure, salt restriction, or pharmacological inhibition of the RAAS, result in an enhancement of renin expression. Elevated renin expression is caused by an increased number of renin-expressing cells (9,49,52,153,166) rather than by gradual increases of renin mRNA in existing renin-producing cells (104). Recruitment of renin-expressing cells (Fig.…”