Hypertension is considered to be a low-grade inflammatory condition characterized by the presence of various proinflammatory cytokines. Tumor necrosis factor-α (TNF-α) is a constituent of the proinflammatory cytokines that is associated with salt-sensitive hypertension (SSH) and related renal injury. Elevated angiotensin II (ANG II) and other factors such as oxidative stress conditions promote TNF-α formation. Many recent studies have provided evidence that TNF-α exerts a direct renal action by regulating hemodynamic and excretory function in the kidney. The cytokine incites a strong natriuretic response and plays a part in regulation of the intrarenal renin-angiotensin system. The exact mechanistic role of TNF-α in the development of SSH is as yet poorly understood. While TNF-α antagonism has been shown to attenuate hypertensive responses in many hypertensive animal models, contrasting findings demonstrate that the direct systemic administration of TNF-α usually induces hypotensive as well as natriuretic responses, indicating a counterregulatory role of TNF-α in SSH. Differential activities of two cell surface receptors of TNF-α (receptor type 1 and type 2) may explain the contradictory functions of TNF-α in the setting of hypertension. This short review will evaluate ongoing research studies that investigate the action of TNF-α within the kidney and its role as an influential pathophysiological variable in the development of SSH and renal injury. This information may help to develop specific TNF-α receptor targeting as an effective treatment strategy in this clinical condition.

Tumor necrosis factor-α (TNF-α) has been implicated in the pathogenesis of hypertension and renal injury. However, the direct effects of TNF-α on renal hemodynamic and excretory function are not yet clearly defined. We examined the renal responses to infusion of TNF-α (0.33 ng·g⁻¹·min⁻¹) in anesthetized mice. Renal blood flow (RBF) and glomerular filtration rate (GFR) were determined by PAH and inulin clearance. The urine was collected from a cannula inserted into the bladder. Following the 60-min control clearance period, TNF-α infusion was initiated and 15 min were given for stabilization followed by another 60-min clearance period. TNF-α alone ( n = 7) caused decreases in RBF (7.9 ± 0.3 to 6.4 ± 0.3 ml·min⁻¹·g⁻¹) and GFR (1.04 ± 0.06 to 0.62 ± 0.08 ml·min⁻¹·g⁻¹) as well as increases in absolute (0.8 ± 0.3 to 1.4 ± 0.3 μmol·min⁻¹·g⁻¹) and fractional excretion of sodium (0.5 ± 0.2 to 1.5 ± 0.4%) without affecting arterial pressure. TNF-α also increased 8-isoprostane excretion (8.10 ± 1.09 to 11.13 ± 1.34 pg·min⁻¹·g⁻¹). Pretreatment with TNF-α blocker etanercept (5 mg/kg sc; 24 and 3 h before TNF-α infusion; n = 6) abolished these responses. However, TNF-α induced an increase in RBF and caused attenuation of the GFR reduction in mice pretreated with superoxide (O₂⁻) scavenger tempol (2 μg·g⁻¹·min⁻¹; n = 6). Pretreatment with nitric oxide (NO) synthase inhibitor nitro-l-arginine methyl ester (0.1 μg·g⁻¹·min⁻¹; n = 6) resulted in further enhancement in vasoconstriction while natriuresis remained unaffected in response to TNF-α. These data suggest that TNF-α induces renal vasoconstriction and hypofiltration via enhancing the activity of O₂⁻and thus reducing the activity of NO. The natriuretic response to TNF-α is related to its direct effects on tubular sodium reabsorption.

Salt sensitive hypertension is characterized by increases in blood pressure in response to increases in dietary salt intake and is associated with an enhanced risk of cardiovascular and renal morbidity. Although researchers have sought for decades to understand how salt sensitivity develops in humans, the mechanisms responsible for the increases in blood pressure in response to high salt intake are complex and only partially understood. Until now, scientists have been unable to explain why some individuals are salt sensitive and others are salt resistant. Although a central role for the kidneys in the development of salt sensitivity and hypertension has been generally accepted, it is also recognized that hypertension is of multifactorial origin and a variety of factors can induce, or prevent, blood pressure responsiveness to the manipulation of salt intake. Excess salt intake in susceptible persons may also induce inappropriate central and sympathetic nervous system responses and increase the production of intrarenal angiotensin II, catecholamines and other factors such as oxidative stress and inflammatory cytokines. One key factor is the concomitant inappropriate or paradoxical activation of the intrarenal renin-angiotensin system, by high salt intake. This is reflected by the increases in urinary angiotensinogen during high salt intake in salt sensitive models. A complex interaction between neuroendocrine factors and the kidney may underlie the propensity for some individuals to retain salt and develop salt-dependent hypertension. In this review, we focus mainly on the renal contributions that provide the mechanistic links between chronic salt intake and the development of hypertension.

Background. Hydrogen sulfide (H2S), an endogenous vasoactive agent, is produced by cystathionine γ-lyase (CGL) and cystathionine β-synthase (CBS) enzym

To examine the potential role of superoxide anion (O ₂ ⁻ ) and its interaction with NO in the regulation of renal hemodynamics and excretory function, we have evaluated the renal responses to enhancement in O ₂ ⁻ activity before and during NO synthase inhibition in anesthetized dogs (n=6). Intraarterial infusion of a superoxide dismutase (SOD) inhibitor, diethyldithiocarbamate (DETC; 0.1 and 0.5 mg/kg per min) was made to enhance O ₂ ⁻ activity in the kidney. Cortical (CBF), medullary (MBF), and total renal blood flow (RBF) responses were assessed using laser-Doppler needle flow probes and an electromagnetic flow probe. DETC caused dose-dependent changes in renal parameters, which were recovered within 30 minutes after the termination of DETC infusion. The high-dose infusion of DETC for 25 minutes resulted in an increase of 29±10% in renal vascular resistance (control, 35.4±4.4 mm Hg/mL per min per g) and decreases of 21±5% in RBF (control, 3.5±0.5 mL/min per g), 20±5% in CBF, 21±7% in MBF, 62±11% in urine flow (control, 10.5±2.2 μL/min per g), and 47±11% in sodium excretion (control, 2.1±0.2 μmol/min per g), without a significant change (−10±6%) in glomerular filtration rate (control, 0.74±0.09 mL/min per g). During NO synthase inhibition with intraarterial administration of nitro- l -arginine (50 μg/kg per min), the same dose of DETC showed a greater increase in renal vascular resistance (73±15%) and reductions in RBF (39±4%), CBF (32±5%), MBF (34±6%), urine flow (78±5%), and sodium excretion (67±10%), with a marked reduction in glomerular filtration rate (59±7%). These data indicate that O ₂ ⁻ exerts renal vasoconstriction as well as antidiuretic and antinatriuretic effects. These responses are enhanced during NO synthase blockade, suggesting that NO serves a renoprotective effect against these action of O ₂ ⁻ .