Renal Effects of Cytokines in Hypertension

Yi Wen; Steven D. Crowley


Curr Opin Nephrol Hypertens. 2018;27(2):70-76. 

In This Article

Conclusion and Future Directions

In the Guytonian view of renal physiology, only impaired clearance of salt and water by the kidney permits sustained elevations in BP.[87] Even in the context of more recent models in which excess sodium is stored nonosmotically in the dermis,[12,13] the kidney still regulates BP through careful titration of intravascular volume. Thus, understanding how inflammatory mediators secreted by hematopoietic cells regulate kidney function is paramount to understanding the immune system's contribution to the pathogenesis of hypertension (Figure 1). Cytokines can modulate salt and water balance by altering sympathetic tone and renal nerve activity, by provoking endothelial dysfunction with secondary effects on renal blood flow, and/or by augmenting sodium transport along the nephron.[49] TGF-β likely has complex actions in the hypertensive kidney because of its dual profibrotic and immunosuppressive functions. On balance, however, the effects of individual cytokines on salt retention and hypertension mirror the inflammatory polarization of the cells from which they are secreted. Thus, proinflammatory T helper 1 and T helper 17 cells and M1 macrophages produce TNF, interleukin 17A, interleukin 1, and IFN, all of which seem to favor BP elevation and/or renal injury when produced endogenously. By contrast, interleukin 10, produced by Tregs, limits the severity of hypertension. VEGF-C and nitric oxide, inasmuch as they facilitate the removal of sodium from the organism, warrant consideration as antihypertensive macrophage 'cytokines'.[12,49] Depending on the dose, distribution, and isoform of the specific cytokines, the preclinical experiments cited above certainly include exceptions to the paradigm in which inflammation begets hypertension. Nevertheless, the general propensity of inflammation to foster BP elevation may represent an evolutionary consequence of the immune system's preventing circulatory collapse in the face of overwhelming infection.

Figure 1.

Renal effects of cytokines in hypertension. Both B cells and DCs participate in the pathogenesis of hypertension through facilitating activation of inflammatory cells. Proinflammatory cytokines including TNF-α, IL-1, IFN-γ, TGF-β, and IL-17 are produced by macrophages and T cells and augment renal function decline and the hypertensive response. By contrast, IL-10 is generated by Th2 cells and Treg and attenuates renal injury and blood pressure elevation. DC, dendritic cells; IFN, interferon; IL, interleukin; TGF, transforming growth factor; TNF, tumor necrosis factor; Treg, T regulatory cells.

The relevance of cytokines to human hypertension will require further evaluation. Circulating levels of certain cytokines correlate with BP in some hypertensive patients,[88] and blocking inflammation and cytokine actions can reduce BP among selected hypertensive patients with rheumatologic disease.[38,39] However, the risk of infection when using immunomodulatory agents in patients with cardiovascular disease is nontrivial.[51] Understanding the precise renal actions of cytokines in hypertension may, therefore, permit us to inhibit cytokine-dependent sodium retention while largely preserving systemic immunity and tumor surveillance. In the meantime, given recent findings that retained salt can reciprocally polarize both T lymphocytes and macrophages toward a heightened inflammatory state,[89–90,91,92] treatment regimens that include diuretics to promote salt excretion together with an anti-inflammatory agent warrant testing in selected patients with hypertension that is sufficiently severe to provoke renal and cardiovascular damage.