Effects of Dietary Salt on Intrarenal Angiotensin System, NAD(P)H Oxidase, COX-2, MCP-1 and PAI-1 Expressions and NF-κB Activity in Salt-Sensitive and -Resistant Rat Kidneys

Abstract

Background: Chronic consumption of a high-salt diet causes hypertension (HTN) and renal injury in Dahl salt-sensitive (SSR) but not salt-resistant rats (SRR). These events are, in part, mediated by oxidative stress and inflammation in the kidney and vascular tissues. Activation of the angiotensin II type 1 (AT₁) receptor plays an important role in the pathogenesis of oxidative stress and inflammation in many hypertensive disorders. However, the systemic renin-angiotensin system (RAS) is typically suppressed in salt-sensitive HTN. This study was designed to test the hypothesis that differential response to a high-salt diet in SSR versus SRR may be related to upregulation of tissue RAS and pathways involved in inflammation and reactive oxygen species (ROS) production. Methods and Results: SSR and SRR were studied 3 weeks after consumption of high- (8%) or low-salt (0.07%) diets. The SSR consuming a low-salt diet exhibited significant increases in AT₁ receptor, cyclooxygenase (COX) 2, plasminogen activator inhibitor (PAI) and phospho-IĸB in the kidney as compared to those found in SRR. The high-salt diet resulted in severe HTN and proteinuria (in SSR but not SRR) and marked elevations of renal tissue monocyte chemoattractant protein 1, p22^phox, NADPH oxidase subunit 4, angiotensin-II-positive cell count, infiltrating T cells and macrophages and further increases in AT₁ receptor, COX-2, PAI-1 and phospho-IĸB in the SSR group. The high-salt diet significantly lowered plasma renin activity (PRA) in SRR but not in the SSR. COX-1 abundance was similar on the low-salt diet and rose equally with the high-salt diet in both groups. Among subgroups of animals fed the low-salt diet, kidney glutathione peroxidase (GPX) abundance was significantly lower in the SSR than SRR. The high-salt diet raised GPX and mitochondrial superoxide dismutase (SOD) abundance in the SRR kidneys but failed to do so in SSR. Cu/Zn-SOD abundance was similar in the subgroups of SSR and SRR fed the low-salt diet. The high-salt diet resulted in downregulation of Cu/Zn-SOD in SSR but not SRR. Conclusions: Salt sensitivity in the SSR is associated with upregulations of the intrarenal angiotensin system, ROS-generating and proinflammatory/profibrotic proteins and an inability to raise antioxidant enzymes and maximally suppress PRA in response to high salt intake. These events can contribute to renal injury with high salt intake in SSR.

Microglia and Monocyte-Derived Macrophages in Stroke

“…Hypertension increases endothelial oxidative stress and inflammation and leads to worse stroke outcomes and higher mortality [210][211][212][213][214][215][216][217][218][219][220]. Studies investigating the underlying pathophysiology of hypertension indicates the involvement of neuroimmune interactions.…”

Redox Control of Renal Function and Hypertension

“…LOX and COX produce oxidative stress through NAD(P)H oxidase-dependent and -independent pathways (29,195). Ang II treatment of rat aortic smooth muscle cells induced 5-lipoxygenase (5-LOX), resulting in an increased production of leukotriene B(4) [LTB(4)].…”

Effects of Intensive Low-Salt Diet Education on Albuminuria among Nondiabetic Patients with Hypertension Treated with Olmesartan

“…In addition, dietary salt increases the glomerular expression of TGF-b1 on renal tissue and also, augments nitric oxide production (14). High salt intake also induces the intrarenal aldosterone receptor and promotes renal fibrotic injury (15). Two recent studies identified that increased dietary salt intake promotes tissue inflammation by triggering IL-17-producing CD4 + T cell development (16,17).…”