Renal Effects of Cytokines in Hypertension

Yi Wen; Steven D. Crowley


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

In This Article

Renal Effects of Cytokines in Hypertension

Tumor Necrosis Factor-α

A prototypical macrophage cytokine, tumor necrosis factor (TNF) is also produced by T cells and resident kidney cells, including renal epithelial cells, mesangial cells, and vascular endothelial cells.[22] Ramseyer et al.[23] recently provided a comprehensive summary of TNF's actions in the kidney. Although infused, TNF exerts a natriuretic effect via ligation of TNF receptor 1,[24,25] the net effect of endogenous TNF is to augment the hypertensive response and associated renal injury in rodent models. For example, TNF deficiency or blockade in mice blunts the chronic hypertensive response to Ang II.[18,26,27] TNF suppresses NOS3-dependent sodium transport in the thick ascending limb,[28] and cross-transplant studies established that these actions of TNF in the kidney exaggerate hypertension in vivo.[26] TNF is directly toxic to glomerular epithelial cells.[29,30] In rats, TNF inhibition attenuates glomerular and tubular injury accruing from hypertension of several causes,[31–33] and infusion of a TNF blocker directly into the renal interstitium can protect against salt-induced BP elevation.[34] Thus, preclinical studies substantiate a role for TNF to promote sodium retention during hypertension, possibly via stimulation of TNF receptor 2 rather than TNF receptor 1,[35] but the local distribution and concentration of TNF within the compartments of the kidney are critical determinants of TNF-dependent BP modulation.

In humans, the effects of TNF on BP have been mixed. In patients with congestive heart failure, TNF inhibition did not reduce BP.[36,37] However, the antihypertensive effects of TNF antagonism may be more easily demonstrated among patients with frank immune activation. Accordingly, in small numbers of hypertensive patients with psoriatic or rheumatoid arthritis, urinary levels of TNF correlated with BP,[38] and TNF blockade with infliximab reduced 24-h ambulatory BP in a crossover study design.[39] Future studies will need to investigate how to vigorously disrupt the actions of TNF that promote sodium retention in the kidney without engendering off-target immunosuppression and loss of tumor surveillance.


Interleukin 1 is an inflammatory cytokine and produced by hematopoietic cells and several resident kidney cell lineages.[40] The two active isoforms of interleukin 1, interleukin 1α, and interleukin 1β, both ligate the same receptor for interleukin 1. An innate signaling complex called the NLRP3 inflammasome cleaves prointerleukin 1β to its active form. Ligation of interleukin 1R1 in turn drives its recruitment of Myd88 and several interleukin 1 receptor-associated kinases that together facilitate translocation of NF-κB's p65 component to the nucleus where it drives the transcription of genes encoding inflammatory proteins, including TNF. A role for interleukin 1 in BP regulation is suggested by the capacity of the NLRP3 components to exacerbate the hypertensive response to several stimuli. For example, deficiency of these components mitigates BP elevation and/or renal injury following Ang II or mineralocorticoid infusion.[41–43] Although infusion of exogenous interleukin 1 promotes a natriuresis,[44–46] endogenous interleukin 1 appears to potentiate hypertension through several actions that could indirectly or directly impact renal function. In the brain, intracisternal injection of interleukin 1 enhances sympathetic outflow causing systemic vasoconstriction, which could impair renal sodium excretion.[46] Interleukin 1 in the systemic or pulmonary vasculature similarly augments pressor responses.[47,48] We found that interleukin 1R1 deficiency or blockade limits NKCC-dependent sodium retention in the thick ascending limb of the nephron and thereby affords partial protection from Ang II-dependent hypertension. In our system, interleukin 1R1 activation promotes the maturation of myeloid cells that in their immature state preserve natriuresis via the elaboration of nitric oxide.[49*] Whether activation of the interleukin 1R1 directly on myeloid cells mediates this phenotypic change is unclear from our experiments, particularly as interleukin 1R1 activation of macrophages favors nitric oxide generation in the setting of infection.[50] Dissecting kidney-specific mechanisms through which interleukin 1 aggravates hypertension will be critical as global interleukin 1 blockade ameliorates cardiovascular disease in humans but increases the susceptibility to fatal infection.[51]


Interferon (IFN) is an inflammatory cytokine, produced by T lymphocytes and macrophages, that drives and marks T-cell differentiation toward a proinflammatory T helper 1 cells subtype and stimulates both macrophages and B cells. IFN enhances sodium transport via the NHE3 transporter in the proximal tubule and via NKCC2 and NCC in the distal nephron.[52] Accordingly, IFN deficiency attenuates the chronic hypertensive response to Ang II.[53] However, abrogating signals via one component of the heterodimeric receptor for IFN (IFNR1) did not impact Ang II-induced BP elevation,[54] suggesting that signaling via the other component of the heterodimer (IFNR2) may be sufficient to preserve IFN-dependent sodium retention. Nevertheless, signaling via IFNR1 appears to be critical for propagating tubulointerstitial inflammation in the kidney during hypertension.[54]

Transforming Growth Factor-β

Transforming growth factor-β (TGF-β) is a key driver of fibrosis in the kidney, particularly during activation of the renin–Ang system (RAS), a prime instigator of hypertension.[45,55] TGF-β triggers renal fibrogenesis by increasing the deposition of extracellular matrix proteins and inhibiting the activity of matrix metalloproteinases.[56–58] Accordingly, chronic administration of recombinant TGF-β1 or TGF-β2 causes renal fibrosis, proteinuria, and elevated BP, presumably because of loss of vascular elasticity and/or impaired natriuresis.[59] Circulating TGF-β levels are increased in Ang II-dependent hypertension.[60] Moreover, in salt-sensitive hypertension, dietary sodium intake may stimulate the renal production of TGF-β.[61,62] Inversely, anti-TGF-β therapy significantly reduces BP, proteinuria, and renal fibrosis in Dahl SS rats.[63,64] Although these studies point to a monolithic, prohypertensive effect of TGF-β in the kidney, TGF-β produced by T regulatory cells (Tregs) may act in concert with interleukin 10, discussed below, to temper BP elevation via the suppression of neighboring T effector lymphocytes.[65] Thus, as with other cytokines, the effects of TGF-β on kidney function in hypertension likely depend on compartmental localization and concentration. Parsing these effects will require incisive experiments, particularly given the complexity and redundancy of the fibrotic signaling pathways downstream of TGF-β.[66]


Interleukin-17A, the founding member of the interleukin 17 family, plays a significant role in infection and autoimmune diseases.[67] Interleukin 17-producing RORrt and CD4+ T cells are the primary source of interleukin 17A, which augments cell-mediated immune responses by stimulating the production of proinflammatory cytokines and chemokines.[68,69] Interleukin 17A induces damage to vascular smooth muscle cells by driving the local generation of ROS, CCL2, interleukin 8, and interleukin 6.[70,71] Madhur et al[72] reported that serum interleukin 17 levels are increased more than three-fold in hypertensive patients compared with healthy controls. In mice, systemic RAS activation augments the elaboration of interleukin 17 by T lymphocytes and triggers the accumulation of interleukin 17 protein in the medial layer of the vessel well.[72] Accordingly, interleukin 17 administration stimulates endothelial dysfunction and BP elevation via a [rho] kinase-dependent pathway.[73] Inversely, interleukin 17A deletion or inhibition, but not blockade of the alternative interleukin 17 isoform, interleukin 17F, inhibits renal and vascular inflammation and BP elevation during chronic Ang II infusion.[72,74] Similarly, deletion of γ-δ T cells, a key source of interleukin 17A, yields protection from experimental hypertension.[75] Within the kidney, interleukin 17A drives sodium reabsorption via the NHE3 exchanger in the proximal tubule and the NCC sodium transporter in the distal convoluted tubule.[76] Thus, the effects of interleukin 17A on vascular remodeling renal sodium handling may synergistically contribute to hypertension. Nevertheless, the tissue and isoform-specific actions of interleukin 17 will require additional clarification as the broad disruption of interleukin 17's effects has had neutral or even detrimental effects on renal damage in some hypertension models.[77,54]


Interleukin 10 is an anti-inflammatory cytokine produced by T helper 2 cells, Tregs, monocytes, and mast cells. Interleukin 10 inhibits activation of NF-κB and limits the production of proinflammatory cytokines and chemokines during hypertension.[78,79] Interleukin 10 administration reduces urinary protein levels, endothelial dysfunction, and BP in rats with pregnancy-induced hypertension.[80–82] Inversely, interleukin 10 deficiency exacerbates endothelial dysfunction and hypertension in TLR3-induced preeclampsia, an effect that is reversed by interleukin 10 supplementation.[83] Following RAS activation, interleukin 10-deficient mice exhibit augmented NADPH oxidase activity and microvascular endothelial dysfunction with variable effects on the hypertensive response.[84–86] Thus, the effects of interleukin 10 to protect the vasculature in preclinical hypertension studies are consistent, but interleukin 10's capacity to modulate BP may depend on whether these vascular effects are sufficient to alter systemic vascular resistance and/or renal sodium handling. Thus, additional studies addressing the precise actions of interleukin 10 in the kidney during hypertension would be informative.