Effects of dietary salt on intrarenal angiotensin system, NAD(P)H oxidase, COX-2, MCP-1 and PAI-1 expressions and NF-kappaB activity in salt-sensitive and -resistant rat kidneys.
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 (AT(1)) 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.


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 AT(1) receptor, cyclooxygenase (COX) 2, plasminogen activator inhibitor (PAI) and phospho-I kappaB 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 AT(1) receptor, COX-2, PAI-1 and phospho-I kappaB 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.
Chandramohan
G
G
Charles R. Drew University of Medicine and Science, Los Angeles, CA, USA.
Bai
Y
Y
Norris
K
K
Rodriguez-Iturbe
B
B
Vaziri
N D
ND
D000804:Angiotensin II / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D018932:Chemokine CCL2 / Q000378:metabolism*; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D006977:Hypertension, Renal / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D020672:I-kappa B Proteins / Q000378:metabolism; D007668:Kidney / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D008264:Macrophages / Q000473:pathology; D008297:Male; D019255:NADPH Oxidases / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism*; D051381:Rats; D020303:Rats, Inbred Dahl; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D012083:Renin / Q000097:blood; D012084:Renin-Angiotensin System / Q000187:drug effects / Q000502:physiology; D017673:Sodium Chloride, Dietary / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000473:pathology
D000975:Antioxidants; C491766:Ccl2 protein, rat; D018932:Chemokine CCL2; C083487:I kappa B beta protein; D020672:I-kappa B Proteins; D016328:NF-kappa B; D017395:Plasminogen Activator Inhibitor 1; D044140:Receptor, Angiotensin, Type 1; D017673:Sodium Chloride, Dietary; D000804:Angiotensin II; D051546:Cyclooxygenase 2; C489691:Ptgs2 protein, rat; D019255:NADPH Oxidases; D012083:Renin