Abstract
Salt-sensitive hypertension is associated with severe organ damage. Generating oxygen radicals is an integral component of salt-induced kidney damage, and activated leukocytes are important in oxygen radical biosynthesis. We hypothesized that a high-salt diet causes the upregulation of immune-related mechanisms, thereby contributing to the susceptibility of Dahl salt-sensitive rats to hypertensive kidney damage. For verifying the hypothesis, we investigated leukocytes adhering to retinal vessels when Dahl salt-sensitive rats were challenged with a high-salt (8% NaCl) diet using acridine orange fluoroscopy and a scanning laser ophthalmoscope. The high-salt diet increased leukocyte adhesion after 3 days and was associated with a significant increase in mRNA biosynthesis of monocyte chemotactic protein-1 and intercellular adhesion molecule-1 (ICAM-1) -related molecules in the kidney. Losartan treatment did not affect increased leukocyte adhesion during the early, pre-hypertensive phase of high salt loading; however, losartan attenuated the adhesion of leukocytes during the hypertensive stage. Moreover, the inhibition of leukocyte adhesion in the pre-hypertensive stage by anti-CD18 antibodies decreased tethering of leukocytes and was associated with the attenuation of functional and morphological kidney damage without affecting blood pressure elevation. In conclusion, a high-salt challenge rapidly increased leukocyte adhesion through the over-expression of ICAM-1. Increased leukocyte adhesion in the pre-hypertensive stage is responsible for subsequent kidney damage in Dahl salt-sensitive rats. Immune system involvement may be a key component that initiates kidney damage in a genetic model of salt-induced hypertension.
Highlights
An increasing number of studies suggest that proinflammatory cytokines released from anchored leukocytes have an important role in the progression of cardiovascular damage in metabolic and hypertensive diseases.[1]
In addition to blood pressure elevation with a high salt intake, leukocyte adhesion slightly increased 2 weeks after the salt challenge; it declined at weeks 3 and 4, whereas blood pressure still increased
Leukocyte adhesion was higher in the high-salt group than in the low-salt group throughout the experiment, while the total number of peripheral leukocytes and their differentiation did not differ between the two groups
Summary
An increasing number of studies suggest that proinflammatory cytokines released from anchored leukocytes have an important role in the progression of cardiovascular damage in metabolic and hypertensive diseases.[1]. In spontaneously hypertensive rats (SHRs), monocyte adhesion in association with the expression of intercellular adhesion molecule-1 (ICAM-1) is increased and the adhesion mechanism in the brain microvasculature mediates the onset of spontaneous hypertension (SHR) and organ damage.[3,4,5,6,7] lipopolysaccharide-stimulated biosynthesis of monocyte chemotactic protein-1 (MCP-1) and ICAM-1/macrophage adhesion ligand-1, a CD-18 receptor and an integral cell-surface protein expressed in most leukocytes, is greater in SHRs than in Wistar Kyoto rats.[8] The adhered leukocytes are less able to suppress immune mechanisms in SHRs.[9]. The oxygen radicals increase leukocyte adhesion through transcription factor nuclear factor kappa B and increased synthesis of the adhesion molecule MCP-1.11 The renin–angiotensin system/oxygen radicals may be responsible for increasing leukocyte adhesion in SHRs
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