The inextricable role of the kidney in hypertension (original) (raw)

A prominent emerging area of hypertension research over the past decade suggests that the immune system may provide an independent cardiovascular control mechanism, whereby its cellular constituents and inflammatory mediators regulate blood pressure. Moreover, we suggest below that immunological effector mechanisms impacting blood pressure can be mapped to the kidney.

Although not rigorously controlled, small clinical studies indicate that broad immunosuppression lowers blood pressure in hypertensive patients with rheumatologic disorders (58), pointing to a role for immune activation in human hypertension. Within the innate immune system, adoptive transfer of monocytes, which are precursors to dendritic cells and macrophages, promotes the hypertensive response to angiotensin II (59). Studies by Guzik and associates convincingly established a role for the adaptive immune response in hypertension pathogenesis, showing that mice with targeted disruption of the recombinase-activating gene-1 (Rag1), and thus lacking T and B cells, were resistant to the development of hypertension induced by chronic infusion of angiotensin II. Adoptive transfer of T but not B cells restored the hypertensive response, clearly illustrating the capacity for T lymphocytes to drive blood pressure elevation (60). Although specific antigens triggering hypertension have not been identified, dual involvement of antigen presenting cells (APCs) and T cells has been well documented. Furthermore, blocking the interaction of B7 ligands on APCs with costimulatory molecules on T cells can abrogate hypertension, indicating that both T cell receptor engagement and costimulation are required (61).

While susceptibility to hypertension primarily depends on CD8+ rather than CD4+ T cells (62), the CD4+ population also may modulate hypertension and hypertensive end-organ damage. In this regard, Th1 cells, a proinflammatory CD4+ T cell subset characterized by expression of the transcription factor Tbet, promote renal damage during hypertension without altering blood pressure (63). Moreover, Th17 cells, another CD4+ subset secreting IL-17, potentiate chronic hypertension (64). In contrast, CD4+ Foxp3+ T regulatory cells, which suppress immune responses, have been reported to protect against hypertension in one study (65), a finding that was not confirmed in work from another group (66). In the first study, three separate doses of T regulatory cells were administered, whereas only one adoptive transfer was performed in the second study, suggesting that the beneficial response may depend on the absolute number of regulatory cells present.

In immune responses, the NF-κB signaling cascade is a prototypical inflammatory pathway mobilizing cytokine transcription and triggering reactive oxygen species (ROS) generation. This pathway seems to play a central role in blood pressure control since its blockade protects against hypertension (67). NF-κB activation within the vascular endothelium drives hypertensive renal damage without measurable effects on blood pressure suggesting a direct role in end-organ damage (68). Within cardiovascular control centers in the brain, NF-κB activation potently enhances sympathetic outflow (69–71), which could potentially promote sodium retention in the kidney via stimulation of renal sympathetic nerves. Within kidney parenchymal cells, induction of oxidative stress leads to NF-κB nuclear translocation, impaired sodium excretion, and blood pressure elevation by disrupting D1 dopamine receptor function (72). Thus, NF-κB signaling may directly contribute to the hypertensive response in kidney cells.

Once activated, macrophages and T cells release cytokines. These soluble mediators may drive blood pressure elevation or mediate end-organ injury in hypertension as illustrated in several experiments using gene knockout models. For example, genetic deletion of the receptor for interferon-γ, the prototypical inflammatory cytokine produced by immune cells, affords protection against end-organ damage in hypertension without altering blood pressure (73). On the other hand, interleukin-6 (IL-6) promotes blood pressure elevation, as mice genetically deficient in IL-6 have a blunted hypertensive response to chronic angiotensin II infusion (74). Finally, tumor necrosis factor-α (TNF-α) seems to have complex effects on blood pressure regulation. In this regard, some studies have shown that genetic deficiency of TNF-α protects against hypertension (60, 75), whereas others indicate TNF-α may have negative or neutral effects on blood pressure (76, 77). Perhaps the influence of TNF-α on blood pressure control may depend on its local levels or the relative expression of its two receptor isoforms (78). In sum, inflammatory cytokines have pleiotropic effects on blood pressure elevation and/or target organ damage in hypertension. As discussed below, several lines of evidence suggest that these cytokines may influence blood pressure by modulating sodium handling by the kidney.

Regardless of the initial trigger for immune activation, immune cells and the inflammatory mediators they secrete appear to alter blood pressure through effects on kidney function. During hypertension, clusters of T lymphocytes infiltrate the adventitia surrounding blood vessels in the kidney, while macrophages disperse throughout the renal interstitium (60, 79, 80). These cells release ROS that can interfere with vascular relaxation to reduce renal blood flow, and thereby diminish sodium excretion following a hypertensive stimulus. Accordingly, scid mice lacking functional T cells have attenuated renal oxidative stress, exaggerated natriuresis, and blunted hypertension during chronic angiotensin II infusion (81). Similarly, preventing infiltration of immune cells into the kidney reduces oxidative stress and lowers blood pressure in rat models of salt-sensitive hypertension (82). Various cytokines prominent in inflammatory responses have direct effects on kidney function. For example, IL-6 stimulates ENaC activity in the collecting duct, promoting sodium retention (83). Similarly, although its role in hypertension is not clearly established, IL-1 stimulates vasoconstriction and modulates sodium excretion (84, 85). Finally, in the thick ascending limb of the loop of Henle, TNF-α suppresses eNOS expression (86), which would enhance sodium retention and increase blood pressure. Thus, in hypertension, T lymphocytes infiltrate the kidney, propagating oxidative stress and the secretion of prohypertensive cytokines, which promotes sodium reabsorption and blood pressure elevation.