Abstract MP24: Selective Activation Of DMV Neurons Improves Renal Injury In Systemic Lupus Erythematosus

Hypertension ◽  
2021 ◽  
Vol 78 (Suppl_1) ◽  
Author(s):  
Caroline G Shimoura ◽  
Cassandra Y Stubbs ◽  
Calvin Brooks ◽  
Keisa W Mathis
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Lupus Erythematosus ◽  
Renal Injury ◽  
Published Data ◽  
Systemic Lupus ◽  
Selective Activation ◽  
Inflammatory Pathway ◽  
Renal Inflammation ◽  
Control Virus ◽  
Anti Inflammatory

The cholinergic anti-inflammatory pathway is a vagally-mediated mechanism that controls inflammation. Our published data suggest that an impaired cholinergic anti-inflammatory pathway contributes to hypertension and renal disease in female mice with systemic lupus erythematosus (SLE), since pharmacological potentiation of the efferent vagus via administration of galantamine reduces renal inflammation, mean arterial pressure (MAP) and glomerulosclerosis. The aim of the current study is to selectively target neurons within the dorsal motor nucleus of the vagus (DMV) to stimulate the efferent vagus and the cholinergic anti-inflammatory pathway using designer receptors exclusively activated by designer drugs (DREADDs). We hypothesized that selective activation of DMV neurons would reduce inflammation, eliminating the associated end organ damage in SLE. To study this, female SLE ( NZBWF1 ) and parental control ( NZW ) mice received bilateral microinjections of pAAV-hSyn-hM3D(Gq)-mCherry or pAAV-hSyn-mCherry (control virus) into the DMV at 31 weeks of age using the following coordinates with calamus as reference: 0 mm caudal, 0.25 mm lateral and 0.48 mm ventral. Two weeks post-microinjection, DREADD agonist CNO (3mg/kg) was administered subcutaneously for 2 weeks starting at 33 weeks. At 35 weeks, mice were housed in metabolic cages for urine collection and catheters were implanted in the carotid artery for MAP measurement. Mice were subsequently euthanized and the brain collected to confirm the site of virus microinjection. Selective activation of DMV neurons decreased the incidence of albuminuria [> 300 mg/dL; 66% (4 out of 6) vs. 0% (0 out of 7)], urinary leukocytes [62.5% (5 out of 8) vs. 50% (3 out of 6)] and blood in the urine [50% (4 out of 8) vs. 16% (1 out of 6)] in SLE mice. MAP did not significantly change with the chemogenetic activation of DMV neurons in SLE mice or parental controls (SLE/control virus: 146 ± 6, n=7; SLE/Gq DREADD: 142 ± 3, n=6; NZW/control virus: 126 ± 4, n=4; NZW/Gq DREADD: 132 ± 2, n=5). These results suggests that this timeline of selective activation of DMV neurons in SLE mice reduces renal injury without altering blood pressure, but future studies will confirm the effect on hypertension and renal inflammation in SLE mice

scholarly journals Pharmacological potentiation of the efferent vagus nerve attenuates blood pressure and renal injury in a murine model of systemic lupus erythematosus

2018 ◽  
Vol 315 (6) ◽  
pp. R1261-R1271 ◽  
Author(s):  
Grace S. Pham ◽  
Lei A. Wang ◽  
Keisa W. Mathis
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Vagus Nerve ◽  
Lupus Erythematosus ◽  
Renal Injury ◽  
Acetylcholinesterase Inhibitor ◽  
Cholinergic Receptor ◽  
Receptor Activation ◽  
Systemic Lupus ◽  
Inflammatory Pathway ◽  
Anti Inflammatory

Recent evidence suggests hypertension may be secondary to chronic inflammation that results from hypoactive neuro-immune regulatory mechanisms. To further understand this association, we used systemic lupus erythematosus (SLE) as a model of inflammation-induced hypertension. In addition to prevalent inflammatory kidney disease and hypertension, SLE patients suffer from dysautonomia in the form of decreased efferent vagal tone. Based on this, the cholinergic anti-inflammatory pathway, an endogenous vagus-to-spleen mechanism that, when activated results in decreases in systemic inflammation, may be compromised in SLE. We hypothesized that stimulation of the cholinergic anti-inflammatory pathway via pharmacological potentiation of the efferent vagus nerve would reduce inflammation and halt the development of hypertension and renal injury in SLE. Female NZBWF1 mice, an established model of murine SLE, and female control mice were treated with galantamine (4 mg/kg daily ip), an acetylcholinesterase inhibitor, or saline for 14 days. At the end of therapy, carotid catheters were surgically implanted and were used to measure mean arterial pressure before the animals were euthanized. Chronic galantamine administration attenuated both splenic and renal cortical inflammation, which likely explains why the hypertension and renal injury (i.e., glomerulosclerosis and fibrosis) typically observed in murine SLE was attenuated following therapy. Based on this, the anti-inflammatory, antihypertensive, and renoprotective effects of galantamine may be mediated through activation of the cholinergic anti-inflammatory pathway. It is possible that dysfunction of the cholinergic anti-inflammatory pathway exists in SLE at the level of the efferent vagus nerve and promoting restoration of its activity through central cholinergic receptor activation may be beneficial.

scholarly journals Systemic Administration of α7-Nicotinic Acetylcholine Receptor Ligands Does Not Improve Renal Injury or Behavior in Mice With Advanced Systemic Lupus Erythematosus

2021 ◽  
Vol 8 ◽  
Author(s):  
Jessica Y. Morales ◽  
Cassandra M. Young-Stubbs ◽  
Caroline G. Shimoura ◽  
William R. Kem ◽  
Victor V. Uteshev ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Nicotinic Acetylcholine Receptor ◽  
Lupus Erythematosus ◽  
Advanced Disease ◽  
Organ Damage ◽  
Systemic Lupus ◽  
Nicotinic Acetylcholine ◽  
Inflammatory Pathway ◽  
Α7 Nachr ◽  
Anti Inflammatory

There is a critical need for safe treatment options to control inflammation in patients with systemic lupus erythematosus (SLE) since the inflammation contributes to morbidity and mortality in advanced disease. Endogenous neuroimmune mechanisms like the cholinergic anti-inflammatory pathway can be targeted to modulate inflammation, but the ability to manipulate such pathways and reduce inflammation and end organ damage has not been fully explored in SLE. Positive allosteric modulators (PAM) are pharmacological agents that inhibit desensitization of the nicotinic acetylcholine receptor (α7-nAChR), the main anti-inflammatory feature within the cholinergic anti-inflammatory pathway, and may augment α7-dependent cholinergic tone to generate therapeutic benefits in SLE. In the current study, we hypothesize that activating the cholinergic anti-inflammatory pathway at the level of the α7-nAChR with systemic administration of a partial agonist, GTS-21, and a PAM, PNU-120596, would reduce inflammation, eliminating the associated end organ damage in a mouse model of SLE with advanced disease. Further, we hypothesize that systemic α7 ligands will have central effects and improve behavioral deficits in SLE mice. Female control (NZW) and SLE mice (NZBWF1) were administered GTS-21 or PNU-120596 subcutaneously via minipumps for 2 weeks. We found that the increased plasma dsDNA autoantibodies, splenic and renal inflammation, renal injury and hypertension usually observed in SLE mice with advanced disease at 35 weeks of age were not altered by GTS-21 or PNU-120596. The anxiety-like behavior presented in SLE mice was also not improved by GTS-21 or PNU-120596. Although no significant beneficial effects of α7 ligands were observed in SLE mice at this advanced stage, we predict that targeting this receptor earlier in the pathogenesis of the disease may prove to be efficacious and should be addressed in future studies.

scholarly journals SAT0211 RENAL INJURY IN SYSTEMIC LUPUS ERYTHEMATOSUS CHARACTERIZED BY THROMBOTIC MICROANGIOPATHY

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 1048.1-1048
Author(s):  
W. Hu
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Lupus Nephritis ◽  
Renal Biopsy ◽  
Lupus Erythematosus ◽  
Thrombotic Microangiopathy ◽  
Renal Injury ◽  
Renal Outcome ◽  
Pathological Examination ◽  
Systemic Lupus ◽  
Tubulointerstitial Lesions

Background:Classical lupus nephritis (LN) is characterized by glomerular immune complex(IC) deposition with glomerular proliferation, basement membrane destruction and cell infiltration. Non-IC mediated renal injury with thrombotic microangiopathy (TMA) was also reported in patients with systemic lupus erythematosus (SLE-renal TMA), but most studies were reported in patients with both LN and renal TMA.Objectives:In this study, clinical features and outcomes of SLE-renal TMA in absence of obvious IC in SLE patients were analyzed.Methods:Patients with glomerular TMA and/or vascular TMA in the absence of obvious subendothelial or epithelial immune deposits were screened out from 2332 biopsied in SLE patients who underwent first renal biopsy from January 2005 to August 2016. Their clinical, histological features and outcomes were retrospectively analyzed.Results:In 2332 renal biopsies obtained from SLE patients, 257 (11.0%) showed renal TMA, of which 237 showed both renal TMA and LN, and 20 biopsies had only renal TMA (SLE-renal TMA). There were 2 males and 18 females with an average age of (25 ± 10) years. The median course of SLE and LN were 3.0(1.0, 6.0) and 0.8(0.5, 1.9) months. All 20 patients deserved acute kidney injury, of which 11 (55%) needed renal replacement therapy (RRT) and 12 (60%) were nephrotic syndrome. Blood system involvement was found in all cases, including 13 cases (65.0%) with TMA triad (microvascular hemolytic anemia, thrombocytopenia and elevated lactate dehydrogenase).Pathological examination showed that 17 cases (85.0%) had both glomerular TMA and vascular TMA. Immunofluorescence and electron microscopy showed that 8 cases (40%) had no IC deposition in glomerulus and 12 cases (60%) had only IC deposition in mesangium. Acute tubulointerstitial lesions in patients requiring RRT were more serious than those no needing for RRT((43.6±24.9) %vs(21.7±20.1) %,P=0.047). The fusion range of foot process was positively correlated with proteinuria (r2= 0.347,P=0.006).All patients received high-dose methylprednisolone pulse therapy. Four patients received plasma exchange and three patients received gamma globulin, respectively. Eleven patients requiring RRT all stop RRT in a median time of 16.0 (9.0, 30.0) days. During a median follow-up of 58.0 (36.0, 92.3) months, complete remission (CR) was obtained in 15 cases, partial remission in 4 cases and no remission in 1 case. Six cases (30%) relapsed. No case died or progressed to end stage renal disease.Conclusion:Renal injury characterized by TMA is not uncommon in SLE renal biopsy cases. The clinical manifestation is special and the renal injury is serious. The renal outcome is good by intensive immunosuppressive therapy. It should be considered as a unique type of renal injury in SLE.References:[1]Moake JL. Thrombotic microangiopathies. N Engl J Med. 2002. 347(8): 589-600.[2]Anders HJ, Weening JJ. Kidney disease in lupus is not always ‘lupus nephritis’. Arthritis Res Ther. 2013. 15(2): 108.[3]Song D, Wu LH, Wang FM, et al. The spectrum of renal thrombotic microangiopathy in lupus nephritis. Arthritis Res Ther. 2013. 15(1): R12.[4]Hu WX, Liu ZZ, Chen HP, Zhang HT, Li LS, Liu ZH. Clinical characteristics and prognosis of diffuse proliferative lupus nephritis with thrombotic microangiopathy. Lupus. 2010. 19(14): 1591-8.[5]Tomov S, Lazarchick J, Self SE, Bruner ET, Budisavljevic MN. Kidney-limited thrombotic microangiopathy in patients with SLE treated with romiplostim. Lupus. 2013. 22(5): 504-9.[6]Li C, Yap D, Chan G, et al. Clinical Outcomes and Clinico-pathological Correlations in Lupus Nephritis with Kidney Biopsy Showing Thrombotic Microangiopathy. J Rheumatol. 2019 .[7]Chen MH, Chen MH, Chen WS, et al. Thrombotic microangiopathy in systemic lupus erythematosus: a cohort study in North Taiwan. Rheumatology (Oxford). 2011. 50(4): 768-75.[8]Park MH, AUID- Oho, Caselman N, Ulmer S, Weitz IC, AUID- Oho. Complement-mediated thrombotic microangiopathy associated with lupus nephritis. Blood Adv. 2018. 2(16): 2090-2094.Disclosure of Interests:None declared

scholarly journals Induction of NF-κB inflammatory pathway in monocytes by microparticles from patients with systemic lupus erythematosus

Heliyon ◽  
2020 ◽  
Vol 6 (12) ◽  
pp. e05815
Author(s):  
Karen Álvarez ◽  
Juan Villar-Vesga ◽  
Blanca Ortiz-Reyes ◽  
Adriana Vanegas-García ◽  
Diana Castaño ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Lupus Erythematosus ◽  
Systemic Lupus ◽  
Inflammatory Pathway

Severe hydralazine-induced lupus presenting as systemic lupus erythematosus

Lupus ◽  
2020 ◽  
Vol 29 (5) ◽  
pp. 509-513 ◽  
Author(s):  
R L Rubin ◽  
R F Haluptzok ◽  
L M Davila
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Lupus Erythematosus ◽  
Systemic Autoimmune Disease ◽  
Systemic Lupus ◽  
Drug Usage ◽  
Drug Induced ◽  
Disease Etiology ◽  
History Of ◽  
Anti Inflammatory ◽  
Symptoms And Signs

Despite its long history of untoward side effects of a systemic autoimmune disease, drug-induced lupus can be difficult to recognize because of the disconnect between chronic drug usage and onset of symptoms. In this case, the patient was treated with hydralazine for two years when symptoms were initially reported, but a diagnosis of hydralazine-induced lupus was not considered for another half year. Despite treatment with steroidal and nonsteroidal anti-inflammatory medications during this period, rheumatologic symptoms and signs continued to deteriorate, consistent with the diagnosis of systemic lupus erythematosus. Not until the patient voluntarily discontinued hydralazine did symptoms begin to improve, fully resolving over the subsequent 6–12 months largely in the absence of anti-inflammatory medication. This patient demonstrates that failure to recognize a drug-induced disease etiology can result in substantial worsening of rheumatologic symptoms over the subsequent six months, ultimately satisfying criteria for systemic lupus erythematosus. While symptoms and signs largely normalized, some laboratory abnormalities and occasional arthralgia remained two years after discontinuing hydralazine, suggesting smoldering inflammatory disease.

scholarly journals Expansion of regulatory T cells using low-dose interleukin-2 attenuates hypertension in an experimental model of systemic lupus erythematosus

2019 ◽  
Vol 317 (5) ◽  
pp. F1274-F1284 ◽  
Author(s):  
Erin B. Taylor ◽  
Jennifer M. Sasser ◽  
Kenji J. Maeda ◽  
Michael J. Ryan
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Mean Arterial Pressure ◽  
Arterial Pressure ◽  
Lupus Erythematosus ◽  
Renal Injury ◽  
Low Dose ◽  
Interleukin 2 ◽  
Autoimmune Disorder ◽  
Systemic Lupus ◽  
And Control

Systemic lupus erythematosus (SLE) is a chronic multisystem autoimmune disorder that is characterized by prevalent hypertension, renal injury, and cardiovascular disease. Numerous studies have reported a low prevalence and/or impaired function of regulatory T (TREG) cells in both patients with SLE and murine models of the disease. Evidence suggests that TREG cell dysfunction in SLE results from a deficiency in IL-2. Recent studies have reported that low-dose IL-2 therapy expands TREG cells in mouse models of SLE, but whether expanding TREG cells protects against hypertension and renal injury during SLE is unclear. To examine this question, female SLE (NZBWF1) and control (NZW) mice were injected with vehicle or recombinant mouse IL-2 three times in 24 h followed by single maintenance doses every 5 days for 4 wk. Treatment with IL-2 effectively expanded TREG cell populations in the peripheral blood, spleen, and kidneys. Circulating levels of anti-dsDNA IgG autoantibodies, a marker of SLE disease activity, were higher in SLE mice compared with control mice but were unaffected by IL-2 treatment. As previously reported by our laboratory, mean arterial pressure, measured in conscious mice by a carotid catheter, was higher in SLE mice than in control mice. Mean arterial pressure was significantly lower in IL-2-treated SLE mice compared with vehicle-treated SLE mice, suggesting that expanding TREG cells using low-dose IL-2 attenuates the development of hypertension. While the mechanism for the protection against hypertension is unclear, it does not appear to be related to the delay of SLE disease progression.

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