Susceptibility to T Cell-Mediated Injury in Immune Complex Disease Is Linked to Local Activation of Renin-Angiotensin System: The Role of NF-AT Pathway

Suzuki, Yusuke; Gómez-Guerrero, Carmen; Shirato, Isao; López-Franco, Óscar; Hernández-Vargas, Purificación; Sanjuán, Guillermo; Ruíz-Ortega, Marta; Sugaya, Takeshi; Okumura, Ko; Tomino, Yasuhiko; Ra, Chisei; Egido, Jesús

doi:10.4049/jimmunol.169.8.4136

Cited by 44 publications

(45 citation statements)

References 69 publications

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“…2, a and b). CD4 ϩ T cell-dependent injury, characterized by mesangial proliferation as described in our recent study (34), was not induced at this dose of NTS in ␥ Ϫ/Ϫ mice. At 5 wk after BM transplantation (day 0), the genotypes of peripheral blood in W␥ and ␥W chimeras were replaced with that of WT or ␥ Ϫ/Ϫ mice, respectively (Figs.…”

Section: Bm-derived Cells Expressing Fcr Play a Crucial Role In The Imentioning

confidence: 83%

Pre-Existing Glomerular Immune Complexes Induce Polymorphonuclear Cell Recruitment Through an Fc Receptor-Dependent Respiratory Burst: Potential Role in the Perpetuation of Immune Nephritis

Suzuki

Gómez-Guerrero

Shirato³

et al. 2003

The Journal of Immunology

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In immune complex (IC) diseases, FcR are essential molecules facilitating polymorphonuclear cell (PMN) recruitment and effector functions at the IC site. Although FcR-dependent initial tethering and FcR/integrin-dependent PMN accumulation were postulated, their underlying mechanisms remain unclear. We here addressed potential mechanisms involved in PMN recruitment in acute IC glomerulonephritis (nephrotoxic nephritis). Since some renal cells may be recruited from bone marrow (BM) lineages, reconstitution studies with BM chimeras and PMN transfer between wild-type (WT) and FcR-deficient mice (γ−/−) were performed. Severe glomerular damage was induced in WT and Wγ chimeras (BM from WT to irradiated γ−/−), while it was absent in γ−/− and γW chimeras (γ−/− BM to WT). Moreover, WT PMN transfer, but not γ−/− PMN, reconstituted the disease in γ−/−, indicating that FcR on resident cells is not a prerequisite for PMN recruitment in this disease. Surprisingly, transferred WT PMN were recruited coincidentally with NF-κB activation and TNF-α overexpression even in glomeruli with preformed IC (nephrotoxic Ab administered 3 days previously), suggesting that PMN can initially be recruited via its own FcR without previous chemoattractant release. Furthermore, H2O2 inhibition by catalase attenuated the acute WT PMN recruitment and the induction of NF-κB and TNF-α much more than integrin (CD18) blockade, indicating a role for the respiratory burst before integrin-dependent accumulation. In coculture experiments with IC-stimulated PMN and glomeruli, PMN caused acute glomerular TNF-α expression predominantly via FcR-mediated H2O2 production. In conclusion, glomerular IC, even preformed, can cause PMN recruitment and injury through PMN FcR-mediated respiratory burst during initial PMN tethering to IC.

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Section: Bm-derived Cells Expressing Fcr Play a Crucial Role In The Imentioning

confidence: 83%

Pre-Existing Glomerular Immune Complexes Induce Polymorphonuclear Cell Recruitment Through an Fc Receptor-Dependent Respiratory Burst: Potential Role in the Perpetuation of Immune Nephritis

Suzuki

Gómez-Guerrero

Shirato³

et al. 2003

The Journal of Immunology

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“…For example, AngII participates in the recruitment of inflammatory cells to a site of injury by direct actions on infiltrating cells and via regulation of expression of adhesion molecules, cytokines, and chemokines (12,36,37). In this study, large numbers of ED-1-positive mononuclear cells were observed in the kidneys of control SHR.…”

Section: Discussionmentioning

confidence: 99%

Long-Term, High-Dosage Candesartan Suppresses Inflammation and Injury in Chronic Kidney Disease

Chen¹,

Gong²,

Rifai

et al. 2007

Journal of the American Society of Nephrology

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Recent evidence suggests that higher-than-usual antihypertensive dosages of renin-angiotensin-aldosterone system blockers may provide additional protection from progression of chronic renal disease; however, there have been few long-term studies, and the underlying mechanisms remain uncertain. This study examined the effects of long-term (14 mo) administration of ultrahigh dosages of the angiotensin receptor blocker candesartan on the progression of renal injury in spontaneously hypertensive rats (SHR). Beginning 8 wk after birth, SHR underwent unilateral nephrectomy and were given vehicle (control), or candesartan at a standard 5 mg/kg per d (T5), high 25 mg/kg per d (T25), or ultrahigh 75 mg/kg per d dosage (T75). After 2 wk, BP was reduced in all treated groups; however, it was better controlled in the high-dosage groups (T25 and T75). Urinary protein was significantly reduced in T75 after 2 wk of treatment and was also declined in the other two treatment groups but only after 2 mo. Exogenous angiotensin II test showed that complete angiotensin receptor blockade was achieved only in the high-dosage groups. Renal inflammation and macrophage (ED-1) infiltration were significantly ameliorated in both T25 and T75 but not in T5 rats. This was associated with the changes of tubular expression of monocyte chemoattractant protein-1, RANTES (regulated upon expression normal T cell expressed and secreted), and the phosphorylated NF-B, a marker for activation. Suppression of ED-1, monocyte chemoattractant protein-1, and RANTES expression and NF-B activation were greater in T75 as compared with T25. These findings suggest that candesartan has dosage-dependent, anti-inflammatory effects that are mediated by suppression of NF-B activation and chemokine expression. Renal protection with high-dosage therapy may depend on these nonhemodynamic effects.

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“…Sequences of the FIRE S1 and S2 double-stranded oligonucleotides (ds-oligos) used for the EMSAs are presented (Fig. 2A); a cognate NFAT site from the mouse IL-2 enhancer (IL-NFAT) served as a positive control (32). As shown in Fig.…”

Section: The Downstream Half Of Fire Is Sufficient To Confer Fast Musclementioning

confidence: 99%

Activity-dependent repression of muscle genes by NFAT

Rana

Gundersen

Buonanno

2008

Proc. Natl. Acad. Sci. U.S.A.

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Adult skeletal muscles retain an adaptive capacity to switch between slow-and fast-twitch properties that largely depend on motoneuron activity. The NFAT (nuclear factor of activated T cells) family of calcium-dependent transcription factors has been implicated in the up-regulation of genes encoding slow contractile proteins in response to slow-patterned motoneuron depolarization. Here, we demonstrate an unexpected, novel function of NFATc1 in slow-twitch muscles. Using the troponin I fast (TnIf) intronic regulatory element (FIRE), we identified sequences that down-regulate its function selectively in response to patterns of electrical activity that mimic slow motoneuron firing. A bona fide NFAT binding site in the TnIf FIRE was identified by site-directed mutations and by electrophoretic mobility and supershift assays. The activity-dependent transcriptional repression of FIRE is mediated through this NFAT site and, importantly, its mutation did not alter the up-regulation of TnIf transcription by fast-patterned activity. siRNA-mediated knockdown of NFATc1 in adult muscles resulted in ectopic activation of the FIRE in the slow soleus, without affecting enhancer activity in the fast extensor digitorum longus muscle. These findings demonstrate that NFAT can function as a repressor of fast contractile genes in slow muscles and they exemplify how an activity pattern can increase or decrease the expression of distinct contractile genes in a use-dependent manner as to enhance phenotypic differences among fiber types or induce adaptive changes in adult muscles.exercise ͉ fiber type ͉ plasticity ͉ troponin T he contractile and metabolic properties of skeletal muscles are determined by both intrinsic and extrinsic cues during development and remain plastic in the adult. Motoneuron and muscle diversity is apparent before innervation and during perinatal development (1-5). Between the first and second postnatal week of rodent development, as polyinnervation is retracted and gap junctions between motoneurons are reduced, motor units begin to depolarize muscles with ''slow'' (tonic, low frequency) and ''fast'' (phasic, high frequency) activity patterns typical of adult motoneurons (6, 7). While activity regulates the expression of contractile proteins that determine the slow and fast twitch properties of adult skeletal muscle fibers, adult muscles remain plastic. Stimulation of fast-twitch muscles with slow-patterned activity causes a fast-toslow fiber-type switching in preexisting fibers, that requires both the up-regulation of slow and repression of fast contractile proteins (8,9).Changes in the contractile properties of skeletal muscles during development and in response to activity occur largely at the transcriptional level (10). Based on studies in neurons and nonneuronal cells, it appears that important information for deciphering patterned activity depends on the location, timing, and dynamics of Ca 2ϩ transients in the cell (11). For example, during T cell lymphocyte activation sustained increases in Ca 2ϩ levels aug...

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Susceptibility to T Cell-Mediated Injury in Immune Complex Disease Is Linked to Local Activation of Renin-Angiotensin System: The Role of NF-AT Pathway

Cited by 44 publications

References 69 publications

Pre-Existing Glomerular Immune Complexes Induce Polymorphonuclear Cell Recruitment Through an Fc Receptor-Dependent Respiratory Burst: Potential Role in the Perpetuation of Immune Nephritis

Pre-Existing Glomerular Immune Complexes Induce Polymorphonuclear Cell Recruitment Through an Fc Receptor-Dependent Respiratory Burst: Potential Role in the Perpetuation of Immune Nephritis

Long-Term, High-Dosage Candesartan Suppresses Inflammation and Injury in Chronic Kidney Disease

Activity-dependent repression of muscle genes by NFAT

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