Transglutaminase is a Critical Link Between Inflammation and Hypertension

Abstract

BackgroundThe pathogenesis of essential hypertension is multifactorial with different underlying mechanisms contributing to disease. We have recently shown that TNF superfamily member 14 LIGHT (an acronym for homologous to lymphotoxins, exhibits inducible expression, and competes with herpes simplex virus glycoprotein D for herpes virus entry mediator, a receptor expressed by T lymphocytes, also known as TNFSF14) induces hypertension when injected into mice. Research reported here was undertaken to examine the role of transglutaminase (TGase) in LIGHT‐induced hypertension.Methods and ResultsInitial experiments showed that plasma and kidney TGase activity was induced by LIGHT infusion (13.91±2.92 versus 6.75±1.92 mU/mL and 19.86±3.55 versus 12.00±0.97 mU/10 μg) and was accompanied with hypertension (169±7.16 versus 117.17±11.57 mm Hg at day 14) and renal impairment (proteinuria, 61.33±23.21 versus 20.38±9.01 μg/mg; osmolality, 879.57±93.02 versus 1407.2±308.04 mmol/kg). The increase in renal TGase activity corresponded to an increase in RNA for the tissue TGase isoform, termed TG2. Pharmacologically, we showed that LIGHT‐induced hypertension and renal impairment did not occur in the presence of cystamine, a well‐known competitive inhibitor of TGase activity. Genetically, we showed that LIGHT‐mediated induction of TGase, along with hypertension and renal impairment, was dependent on interleukin‐6 and endothelial hypoxia inducible factor‐1α. We also demonstrated that interleukin‐6, endothelial hypoxia inducible factor‐1α, and TGase are required for LIGHT‐induced production of angiotensin receptor agonistic autoantibodies.ConclusionsThus, LIGHT‐induced hypertension, renal impairment, and production of angiotensin receptor agonistic autoantibodies require TGase, most likely the TG2 isoform. Our findings establish TGase as a critical link between inflammation, hypertension, and autoimmunity.

Transglutaminase 2 in pulmonary and cardiac tissue remodeling in experimental pulmonary hypertension

“…Recent evidence indicates that TG2-mediated cross-linked extracellular matrix protein collagen has been shown to induce nuclear translocation and transcriptionally activate YAP/TAZ in stromal fibroblasts promoting cancer cell proliferation (19). We have already demonstrated that TG2 participates in PA smooth muscle cell proliferation (29), and others have shown that inflammatory processes that occur in PH (31, 36) also may regulate TG2 expression (24). Furthermore, PH has been identified more Fig.…”

Inflammation, Autoimmunity, and Hypertension: The Essential Role of Tissue Transglutaminase

“… 28 , 42 LIGHT is significantly higher in the circulation of women with preeclampsia, a serious hypertensive condition of pregnancy, and is able to induce hypertension when introduced into pregnant or nonpregnant mice. 28 , 43 …”

“…Subsequent experiments showed that IL-6 is required for LIGHT/TNFSF14-induced hypertension and AT1-AA production in nonpregnant mice. 43 These inflammatory cytokines establish a causal link between inflammation and autoimmunity in the pathogenesis of hypertensive disorders and provide a convenient experimental animal model to determine the mechanism of cytokine-induced autoantibody production and the contribution of these autoantibodies to hypertension.…”

The Influence of Hypertensive Therapies on Circulating Factors: Clinical Implications for SCFAs, FGF21, TNFSF14 and TNF-α

“…We examined the comparative levels of TNF family members in this human cohort as increases in TNFSF14 [ 20 ] and TNF-α [ 21 ] levels have both been shown to be associated with elevated BP ( Figure 3 ). The circulating levels of TNFSF14 were higher in the untreated hypertensive (158.59 ± 71.77 pg/mL) group in comparison to the normotensive (82.29 ± 28.76 pg/mL) group.…”

“…In women with preeclampsia, a serious hypertensive condition of pregnancy, an elevated level of circulating TNFSF14 has been detected [ 14 ]. It was subsequently shown in mouse models that the administration of TNFSF14 could induce hypertension [ 20 ]. In our cohort, we found elevated levels of serum TNFSF14 in untreated hypertensive patients compared to the normotensive subjects, which may be directly contributing to the rise in BP.…”