Abstract
Tumor necrosis factor α (TNFα) is a major proinflammatory cytokine and its level is elevated in hypertensive states. Inflammation occurs in the kidneys during the development of hypertension. We hypothesized that TNFα specifically in the kidney contributes to the development of hypertension and renal injury in Dahl salt-sensitive (SS) rats, a widely used model of human salt-sensitive hypertension and renal injury. SS rats were chronically instrumented for renal interstitial infusion and blood pressure measurement in conscious, freely moving state. Gene expression was measured using real-time PCR and renal injury assessed with histological analysis. The abundance of TNFα in the renal medulla of SS rats, but not the salt-insensitive congenic SS.13BN26 rats, was significantly increased when rats had been fed a high-salt diet for 7 days (n = 6 or 9, p < 0.01). The abundance of TNFα receptors in the renal medulla was significantly higher in SS rats than SS.13BN26 rats. Renal interstitial administration of Etanercept, an inhibitor of TNFα, significantly attenuated the development of hypertension in SS rats on a high-salt diet (n = 7–8, p < 0.05). Glomerulosclerosis and interstitial fibrosis were also significantly ameliorated. These findings indicate intrarenal TNFα contributes to the development of hypertension and renal injury in SS rats.
Highlights
Hypertension is a major public health issue[1]
Congenic SS.13BN26 rats, which we have shown to exhibit a lower level of blood pressure salt-sensitivity compared to SS rats[25,36], were used as salt-insensitive control
Tumor necrosis factor α (TNFα) abundance increased significantly in SS rats treated with 4% (n = 9) or 8% (n = 6) NaCl diet for 7 days, and this change occurred between 3 and 7 days of 8% NaCl diet (Fig. 1A,B)
Summary
Hypertension is a major public health issue[1]. Salt is one of the major environmental factors that contribute to the development of hypertension[2]. Pharmacological or genetic manipulations that inhibit inflammation and immune response reduce renal interstitial infiltration of immune cells and attenuate salt-induced hypertension and renal injury in SS rats as well as in other models[7,8,9,10]. Systemic administration of Etanercept, a soluble recombinant fusion protein that blocks the functional effect of TNFα , attenuates the development of hypertension and renal injury in several models[13,14,15]. It is not clear, whether TNFα in the kidney contributes to hypertension. Gene name 18s rRNA TNFα Tnfrsf1A Tnfrsf1B forward primer reverse primer forward primer reverse primer forward primer reverse primer forward primer reverse primer
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