Should Renal Inflammation Be Targeted While Treating Hypertension?

Abstract

Despite extensive research and a plethora of therapeutic options, hypertension continues to be a global burden. Understanding of the pathological roles of known and underexplored cellular and molecular pathways in the development and maintenance of hypertension is critical to advance the field. Immune system overactivation and inflammation in the kidneys are proposed alternative mechanisms of hypertension, and resistant hypertension. Consideration of the pathophysiology of hypertension in chronic inflammatory conditions such as autoimmune diseases, in which patients present with autoimmune-mediated kidney inflammation as well as hypertension, may reveal possible contributors and novel therapeutic targets. In this review, we 1) summarize current therapies used to control blood pressure and their known effects on inflammation; 2) provide evidence on the need to target renal inflammation, specifically, and especially when first-line and combinatory treatment efforts fail; and 3) discuss the efficacy of therapies used to treat autoimmune diseases with a hypertension/renal component. We aim to elucidate the potential of targeting renal inflammation in certain subsets of patients resistant to current therapies.

Keywords: autoimmunity; blood pressure; immune cells; kidney; lupus; resistant hypertension; systemic lupus erythematosus.

FIGURE 1

The pathophysiology of SLE-induced hypertension: A summary of factors that contribute to hypertension in SLE. Inflammation due to autoimmunity (red), as well as humoral factors that increase it (purple), and aberrant activity causing oxidative stress (green) comprise endogenous causes of lupus hypertension. The cholinergic anti-inflammatory pathway (blue) represents a neurogenic cause of lupus hypertension. Arrows (→) indicate stimulation; line with flathead (--|) indicates inhibition (RAS- renin angiotensin system; α7nAchRs-alpha seven nicotine acetyl choline receptors).

FIGURE 2

Cholinergic anti-inflammatory pathway reduces renal inflammation and hypertension: The afferent vagus nerve detects inflammatory cytokines and relays this information centrally to increase the efferent vagus, which synapses on the celiac ganglion and activates the splenic nerve. Another possible mechanism for activation of splenic nerve is via the splanchnic nerve. The splenic nerve has sympathetic fibers and stimulates splenic ChAT + T cells to synthesize and secrete acetylcholine, which acts upon various immune cells in the spleen, including macrophages, to inhibit the production and release of inflammatory cytokines. A reduction in splenic inflammation and proinflammatory cytokines in circulation decreases renal inflammation and renal injury preventing the rise in the blood pressure. The efferent vagus nerve can be stimulated using pharmacological agents galantamine and CNI-1493 or direct electrical stimulation. GTS-21 and nicotine, agonists of the α7nAchR and PNU-120596, positive allosteric modulator for this receptor leads to activation of this receptor to inhibit the cytokine release from immune cells. (β2AR—beta 2 adrenergic receptor; ChAT + T cells—choline acetyltransferase positive T cells; α7nAchRs—alpha seven nicotine acetylcholine receptors). Created with Biorender.com.