IgA Nephropathy Benefits from Compound K Treatment by Inhibiting NF-κB/NLRP3 Inflammasome and Enhancing Autophagy and SIRT1.

IgA nephropathy (IgAN), the most common primary glomerular disorder, has a relatively poor prognosis yet lacks a pathogenesis-based treatment. Compound K (CK) is a major absorbable intestinal bacterial metabolite of ginsenosides, which are bioactive components of ginseng. The present study revealed promising therapeutic effects of CK in two complementary IgAN models: a passively induced one developed by repeated injections of IgA immune complexes and a spontaneously occurring model of spontaneous grouped ddY mice. The potential mechanism for CK includes 1) inhibiting the activation of NLRP3 inflammasome in renal tissues, macrophages and bone marrow-derived dendritic cells, 2) enhancing the induction of autophagy through increased SIRT1 expression, and 3) eliciting autophagy-mediated NLRP3 inflammasome inhibition. The results support CK as a drug candidate for IgAN.

Treatment effects of Chinese medicine (Yi-Qi-Qing-Jie herbal compound) combined with immunosuppression therapies in IgA nephropathy patients with high-risk of end-stage renal disease (TCM-WINE): study protocol for a randomized controlled trial.

BACKGROUND: IgA nephropathy (IgAN) is the most common glomerular disease worldwide. It has a high incidence in Asians and is more likely to progress to end-stage renal disease (ESRD). For high-risk IgAN, which is clinically characterized by massive proteinuria and renal dysfunction, however, there has been no international consensus on treatment options. Compared with other developed countries, IgAN patients in China are often found to have severe kidney function loss at initial diagnosis. Yi-Qi-Qing-Jie formula (YQF; a compound recipe of Chinese medicinal herbs) has shown potential renal protection in our previous clinical studies. To further confirm the efficacy and safety of YQF in the treatment of high-risk IgAN, we have designed a prospective double-blind randomized placebo-controlled trial. METHODS/DESIGN: The TCM-WINE study is a single-center, prospective, double-blind randomized placebo-controlled trial. We plan to randomize 60 participants with biopsy-proven IgAN to a YQF combined group (YQF compound combined with prednisolone, and cyclophosphamide if necessary) or an immunosuppression group (placebo-YQF combined with prednisolone, and cyclophosphamide if necessary). The two groups will enter a 48-week in-trial treatment phase and receive post-trial follow-up until study completion (3 years). All patients will receive optimal supportive care. The primary composite outcome is defined as the first occurrence of a 40% decrease in estimated glomerular filtration rate (eGFR) from the baseline lasting for 3 months, initiating continuous renal replacement treatment, or death due to chronic kidney disease (CKD) during the 3-year study phase. The secondary endpoint events are defined as the mean annual eGFR decline rate (eGFR slope, ml/min per 1.73 m2 per year), which is calculated by the eGFR regression curve for each eligible patient, and proteinuria remission (prescribed as proteinuria < 0.5 g/day) at weeks 24, 36, and 48 during the in-trial phase. The remission rate of symptoms and inflammation status will be evaluated at week 48. Safety monitoring and assessment will be undertaken during the study. DISCUSSION: The TCM-WINE study will evaluate the effects and safety of YQF combined therapy compared with immunosuppression monotherapy on the basis of the optimal supportive treatment in high-risk IgAN. The evidence from this study will provide a novel, effective, and safe Chinese characteristic therapy for high-risk IgAN patients. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03418779. Registered on 18 June 2018.

A Proliferation Inducing Ligand (APRIL) targeted antibody is a safe and effective treatment of murine IgA nephropathy.

IgA nephropathy (IgAN) is the most prevalent primary chronic glomerular disease for which no safe disease-specific therapies currently exist. IgAN is an autoimmune disease involving the production of autoantigenic, aberrantly O-glycosylated IgA1 and ensuing deposition of nephritogenic immune complexes in the kidney. A Proliferation Inducing Ligand (APRIL) has emerged as a key B-cell-modulating factor in this pathogenesis. Using a mouse anti-APRIL monoclonal antibody (4540), we confirm both the pathogenic role of APRIL in IgAN and the therapeutic efficacy of antibody-directed neutralization of APRIL in the grouped mouse ddY disease model. Treatment with 4540 directly translated to a reduction in relevant pathogenic mechanisms including suppressed serum IgA levels, reduced circulating immune complexes, significantly lower kidney deposits of IgA, IgG and C3, and suppression of proteinuria compared to mice receiving vehicle or isotype control antibodies. Furthermore, we translated these findings to the pharmacological characterization of VIS649, a highly potent, humanized IgG2κ antibody targeting and neutralizing human APRIL through unique epitope engagement, leading to inhibition of APRIL-mediated B-cell activities. VIS649 treatment of non-human primates showed dose-dependent reduction of serum IgA levels of up to 70%. A reduction of IgA+, IgM+, and IgG+ B cells was noted in the gut-associated mucosa of VIS649-treated animals. Population-based modeling predicted a favorable therapeutic dosing profile for subcutaneous administration of VIS649 in the clinical setting. Thus, our data highlight the potential therapeutic benefit of VIS649 for the treatment of IgAN.

Immunoglobulin A Nephropathy and Immunoglobulin A Vasculitis.

Henoch-Schönlein purpura nephritis and immunoglobulin A nephropathy are common glomerulopathies in the pediatric population that deserve special attention. In some cases the primary care provider can follow the patient but others need more intensive management. Delaying this treatment can lead to worse morbidity. This article provides information on the pathogenesis, outcomes, and follow-up strategies that will aid in the diagnosis and referral of patients at risk for kidney disease.

[Considerations on the treatment of IgA nephropathy on the basis of the results of the latest studies (STOP-IgAN, TESTING, NEFIGAN)]. / Terápiás megfontolások IgA-nephropathiában a legutolsó vizsgálatok (STOP-IgAN, TESTING, NEFIGAN) eredményei alapján.

IgA nephropathy is an immune-mediated chronic glomerulonephritis with a great variability in clinical presentation and outcome. The disease can progress to end-stage renal failure in 25% of patients. For this reason we should identify patients with potential to progress. Most important risk factors for progression are persistent proteinuria, hypertension, decreased renal function and some histological lesions. The actually suggested treatment is summarized in KDIGO Clinical Practice Guideline from 2012. They suggest to give firstly non-specific supportive treatment (especially renin-angiotensin system blocking agents). Recommendation about steroid/immunosuppression treatment is based on low level of evidence. Recently three studies were organised concerning benefits and risk of steroid/immunosuppressive treatment added together with specific supportive treatment. In the STOP-IgAN study, systemic steroid/immunosuppressive treatment significantly decreased proteinuria but did not stop progression. In the TESTING study, systemic steroid treatment significantly decreased proteinuria and progression. However, the study was recently discontinued due to several severe side effects of steroid treatment. Involvement of intestinal mucosal immunity in the pathogenesis of IgA nephropathy suggested the NEFIGAN study with budesonide treatment. Budesonide releases corticosteroid in distal small intestine and colon. Proteinuria was significantly decreased and renal function remained stabile. High number of withdrawals owing to adverse effects is a major concern implying a substantial systemic effect of budesonide. We need further information on the characteristics of patients who most likely benefit from steroid/immunosuppressive treatment given after or together with specific supportive treatment. Orv Hetil. 2017; 158(49): 1946-1952.

[Effect of "Gubentongluo Formula" on the IgA Class Switch Recombination of B Lymohocytes in Peyer's Patches in Mice with IgA Nephropathy].

OBJECTIVE: To explore the underlying mechanism of "Gubentongluo Formula" in treatment of IgA nephropathy (IgAN). METHODS: After the IgAN model was successfully induced at week 12, the Kunming mice were randomly divided into three groups: normal control group (n = 15), IgAN group (n = 15) and Traditional Chinese Medicine (TCM) group. The mice in normal control and IgAN group were intragastriclly administrated with normal saline for 8 weeks; meanwhile, the mice in TCM group were intragastriclly administrated with "Gubentongluo Formula" 1.35 mL/ (g · d). The levels of 24 h urine protein were determined at Week 0, 12 and 20. At week 20, the changes of renal pathology were detected; the mRNA expressions of transforming growth factor-ß (TGF-ß) and small mothers against decapentaplegic (Smad) 3 in Peyer's patches (PPs) were detected by fuorescent quantitative reverse transcription-polymerase chain reaction; the protein expressions of TGF-ß and Smad 3 in PPs were detected by immunohistochemistry technique; the levels of (IgA + B)/B lymphocytes in PPs were determined by flow cytometry. RESULTS: Compared with those results of normal control group, the levels of 24 h urine protein, IgA deposition in glomerular mesangial area, and expressions of protein and mRNA of TGF-ß and Smad3 in IgAN group were significantly increased (P < 0.01). Besides, the levels of (IgA+B)/B lymphocytes were significantly elevated in IgAN group (P < 0.01). All these indicators were improved in TCM group. Compared with IgAN group, the differences were statistically significant (P < 0.01). Compared with those results of control group, the levels of (IgA + B)/B lymphocytes showed no significant difference in TCM group (P > 0.05), but other indicators showed significant differences (P < 0.01). CONCLUSION: "Gubentongluo Formula" could effectively improve proteinuria and suppress IgA deposition in glomerular mesangial area in IgAN mice, due to affect IgA class switch recombination of B lymphocytes in PPs through regulating TGF-ß/Smad3 pathway.

Efficacy of triptolide on the apoptosis of tonsillar mononuclear cells from patients with IgA nephropathy.

AIMS: This study aimed to evaluate the extent of apoptosis of tonsillar mononuclear cells (TMCs) derived from patients with IgA nephropathy (IgAN) and the effects of triptolide (TP) on the apoptosis of these TMCs. METHODS: TMCs were isolated from tonsillar tissues of patients with IgAN or chronic tonsillitis (control group). Rates of TMCs apoptosis were measured by annexin V-fluorescein isocyanate (FITC)/propidium iodide (PI)-labeled flow cytometry (FCM). Expression levels of Bcl-2 family proteins were quantified by immunohistochemistry of fixed tonsillar sections and Western blot analyzes of TMCs lysates. TMCs from IgAN patients were treated 10, 20, or 30 ng/mL TP for 24 h and then evaluated for viability by the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay, for the percentage of apoptotic cells by FCM, and for the relative expression levels of Bcl-2 family proteins by Western blot analysis. RESULTS: Compared to TMCs from the control group, TMCs from the IgAN group demonstrated lower rates of apoptosis, higher expression levels of the anti-apoptosis proteins Bcl-2 and Bcl-xL, and lower expression levels of the pro-apoptosis protein Bax. Treatment of IgAN patient-derived TMCs with 10, 20, or 30 ng/mL TP for 24 h suppressed the viability and promoted the apoptosis of TMCs in a dose-dependent manner. Western blot analysis revealed a TP dose-dependent decrease in Bcl-2 and Bcl-xL expression levels, in parallel with increased Bax protein levels. CONCLUSION: TMCs from IgAN patients may be in a state of inhibited apoptosis mediated by Bcl-2 family proteins, which may be reversed by TP treatment.

Treating IgA nephropathy: quid novi?

IgA nephropathy is a common autoimmune renal disease resulting in kidney failure for patients with significant proteinuria. The therapeutic options are limited including non-specific treatment to reduce proteinuria accomplished by renin-angiotensin blockade. Strategies to control intrarenal inflammation include the administration of fish oil and for severe disease the use of immunosuppressive agents such as cyclophosphamide, glucocorticosteroids, and mycophenolate mofetil. In light of the limited option, there is an unmet need for novel therapeutic intervention in patients with progressive disease. Herein, we review the evidence for existing treatment choices and explore new immunopharmacologic agents being investigated for IgA nephropathy.

Dietary zinc is a key environmental modifier in the progression of IgA nephropathy.

IgA nephropathy (IgAN) shows diverse epidemiological characteristics, resulting from both genetic and acquired (e.g., environmental) causes. Environmental factors, such as diet or exposure to exogenous antigens, may prescribe the progression or prognosis of IgAN. It remains unclear as to how diet and infection influence susceptibility to IgAN. A relationship, such as Toll-like receptors (TLRs), especially TLR9 and TLR4, was demonstrated between IgAN and pathogen-recognition molecules. Recently, zinc (Zn) was discovered to be involved in various immune-related diseases, affecting B, T, and dendritic cells (DCs). This study investigates the relationship between dietary Zn and IgAN development in IgAN-prone mice. Seven-week-old IgAN-prone mice were divided into low, normal, and high Zn diet groups. To assess exogenous pathogen-mediated immune responses, lipopolysaccharide (LPS) was nasally administered. The activity of IgAN was biochemically and pathologically evaluated during the disease course. We also examined in vitro IgA production in spleen cells or in combinations of cocultured B, T, and DCs under various Zn conditions with or without LPS. Dietary conditioning with Zn affected serum immunoglobulins and urinary albumin levels, and mesangial deposition of IgA and IgG. Zn deficiency is associated with IgAN progression through the activation of the TLR4/TIR-domain-containing adapter-inducing interferon-ß (TRIF), but not the TLR9, in DCs. Zn supplementation prevented disease aggravation. Our findings indicate that immune conditioning with dietary Zn alters nephritogenic IgA production after mucosal infection.

Potential of renal pathology on refining syndrome typing of Chinese medicine in IgA nephropathy.

OBJECTIVE: To investigate the potential of renal pathological index as a differential diagnosis factor for Chinese medicine (CM) syndromes typing in IgA nephropathy (IgAN). METHODS: A total of 1,016 patients with IgAN was recruited from November 2001 to November 2004. All the signs and symptoms including picture of the tongue and pulse tracings were collected. All patients were typed according to the CM syndrome typing scheme for chronic primary glomerulopathy. The severity of glomerulus and tubulointerstitial lesions (mild, moderate-severe) were evaluated using lee's grading system and the Katafuchi score system. RESULTS: The syndrome types transform in turn by deficiency of both the Spleen (Pi) and Lung (Fei) qi, deficiency of both qi and yin, deficiency of Liver (Gan) and Kidney (Shen) yin and deficiency of Spleen-Kidney (Shen) yang, with the aggravation of pathogenetic condition and that the manifestation of deficiency of qi clinically showed proliferative lesion of glomerular mesangium, while the glomerular sclerosis pathologically showed the manifestation of yin deficiency. CONCLUSION: Renal pathological findings may be a candidate of objective factors to refine CM syndrome typing process.

Treatment of IgA nephropathy: an update.

OBJECTIVE: To review current literature regarding treatment options for immunoglobulin A nephropathy (IgAN). DATA SOURCES: A MEDLINE search was performed using the terms IgA nephropathy, Berger's disease, immunoglobulin A nephropathy, angiotensin converting enzyme inhibitors, angiotensin II receptor blockers, fish oil, omega-3 fatty acids, statins, hydroxymethylglutaryl-CoA reductase inhibitors, immunosuppressive therapy, corticosteroids, mycophenolate mofetil, cyclophosphamide, cyclosporine, azathioprine, leflunomide, antiplatelets, anticoagulants, vitamin E, infliximab, calcitriol, and intravenous immunoglobulins. A date limit was not set; however, focus was on publications from 1999 to June 2011 to review recent literature and therapeutic recommendations. STUDY SELECTION AND DATA EXTRACTION: All articles in English, including studies conducted in humans, meta-analyses, review articles, guidelines, statements, and reference citations, were identified and evaluated. DATA SYNTHESIS: IgAN is the most common primary glomerulonephritis worldwide, leading to end-stage renal disease in 20-30% of patients. Evidence guiding management of IgAN has been sparse and clinical trials have not conclusively demonstrated effective treatments, largely due to suboptimal methodologies. Treatment strategies have included management of blood pressure and lipids, improvement or stabilization of kidney function, and reduction of proteinuria. This review of IgAN provides an update regarding standard and nonconventional treatment options based on recently published literature. CONCLUSIONS: Supportive therapies, including angiotensin blockade, should be considered as first-line therapy for patients with urine protein >0.5 g/day and/or blood pressure >140/90 mm Hg. Corticosteroids could be considered as add-on or monotherapy for patients with urine protein >1 g/day with preserved renal function. Conclusive data are lacking for general treatment recommendations for the use of other therapies for IgAN.

Meta-analysis of Tripterygium wilfordii Hook F in the immunosuppressive treatment of IgA nephropathy.

OBJECTIVE: Numerous Chinese patients with IgA nephropathy (IgAN) have benefited from Tripterygium wilfordii Hook F (TwHF) from two decades ago. However, to date there is no systematic evaluation of this remedy for IgAN. METHODS: We conducted a meta-analysis of all eligible randomized clinical trials (RCTs) to assess the effect of TwHF on IgAN for the first time. In August 2009 a systematic search was performed among eight electronic databases. Review Manager (RevMan) version 5.0 was used. RESULTS: (i) Four eligible RCTs with 188 participants were included; (ii) The validities of included RCTs were generally acceptable; (iii) TwHF brought about a favorable increase in complete remission (CR) (RR 1.53, 95%CI 1.09 to 2.16, I(2)=12%) and total remission (TR) (RR 1.27, 95%CI 1.08 to 1.48, I(2)=0%) compared with non-TwHF treatment; and this result was further confirmed by intention-to-treat analysis; (iv) Exploiting subgroup meta-analysis, TwHF led to significantly greater improvements of IgAN with non-nephrotic proteinuria with regard to the increase of CR (RR 1.80, 95%CI 1.21 to 2.68, I(2)=0%) and TR (RR 1.32, 95%CI 1.11 to 1.57, I(2)=0%), and decrease of urinary proteinuria excretion (UPE) (MD -467.41 mg/24h, 95%CI -633.99 to -300.82, I(2)=0%). Meanwhile, the renal function was well preserved (MD -2.66 µmol/L, 95%CI -9.26 to 3.94, I(2)=0%). Conclusion Although the results of this meta-analysis should be interpreted with caution and warrant further investigation, TwHF was certainly a valuable and promising immunosuppressive remedy for IgAN, which was in accordance with the accruing evidence from numerous large clinical and experimental studies.

n-3 polyunsaturated fatty acids and autoimmune-mediated glomerulonephritis.

Consumption of n-3 polyunsaturated fatty acids (PUFAs) found in fish oil suppresses inflammatory processes making these fatty acids attractive candidates for both the prevention and amelioration of several organ-specific and systemic autoimmune diseases. Both pre-clinical and clinical studies have been conducted to determine whether fish oils containing the n-3 PUFAs docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) can be used in the prevention and treatment of immunoglobulin A nephropathy (IgAN) and lupus nephritis. In a toxin-induced mouse model that mimics the early stages of IgAN, n-3 PUFA consumption suppresses aberrant interleukin (IL)-6-driven IgA production and mesangial IgA immune complex deposition by impairing phosphorylation of upstream kinases and activation of transcription factors essential for IL-6 gene transcription. n-3 PUFAs can also suppress production of anti-double-stranded DNA IgG antibodies and the resultant development of lupus nephritis in the NZBW F1 mouse and related models. These effects have been linked in part to impaired expression of proinflammatory cytokines and adhesion molecules as well as increases in antioxidant enzymes in kidney and immune organs. Several recent clinical trials have provided compelling evidence that n-3 PUFA supplementation could be useful in treatment of human IgAN and lupus nephritis, although some other studies suggest such supplementation might be without benefit. Future investigations employing genomics/proteomics and novel genetically altered mice should provide further insight into how n-3 PUFAs modulate these diseases as well help to identify clinically relevant biomarkers. The latter could be employed in future well-designed, long-term clinical studies that will resolve current controversies on n-3 PUFA efficacy in autoimmune-mediated glomerulonephritis.

[Regulatory effect of Astragalus membranaceus on the immune disorder in rats with IgA nephropathy].

OBJECTIVE: To study the regulattory effect of Astragalus membranaceus on immune disturbance of the rats with IgA nephropathy. METHODS: Rats IgA nephropathy (IgAN) model was duplicated by oral feeding of bovine serum albumin (BSA), subcutaneous injection of carbon tetrachloride (CCl4) and injection of lipopolysaccharide (LSP) into vena caudalis. The rats were divided into three groups randomly for the normal, IgAN model group and the group treated with Astragalus membranaceus (treatment group). The treatment group was given the Astragalus membranaceus granules via intragastric administratsion, the normal group and the IgAN model group were given the equal amount of aqua destillata by gastric perfusion. The rats were examined for albuminuria, hematuria and pathological changes of renal tissue and the distribution of TGF-beta and interleukin-5 in renal tissue was determined by immunohistochemistry and the IFN-gamma and IL-4 of cytokine of Th1 and Th2 types were detected in rats IgA nephropathy model by sandwich enzyme linked immunosorbent assay (ELISA). RESULTS: (1) The hematuria in rats with IgA nephropathy significantly increased compared with normal control group and Astragalus treatment group (P < 0.05). There was significant increase in albuminuria in rats with IgA nephropathy, compared with normal control group and astragalus treatment group (P < 0.01). (2) The pathological change of glomerular mesangium, renal tubules and renal interstitia became serious in rats IgA nephropathy model when compared with normal control group and astragalus treatment group. Immumofluorescence showed renal IgA density in rats IgA nephropathy model was significantly higher than that in the normal control group (P < 0.001) and astragalus treatment group (P < 0.001). (3) The result of immuno histochemistry showed that there was only weak expression of TGF-beta and interleukin 5 in normal renal tissue. The expression of TGF-beta and interleukin 5 in IgA nephropathy model was significantly stronger than those in normal control group (P < 0.05) and astragalus treatment group (P < 0.05). (4) The serum IL-4 levels were (33.74 +/- 7.52) pg/ml in rats IgA nephropathy model, significantly higher than that in normal control group (2.36 +/- 0.85) pg/ml and astragalus treatment group (3.24 +/- 1.13) pg/ml. The IFN-gamma level in serum of rats IgA nephropathy model was (18.79 +/- 3.80) pg/ml, which was significantly higher than that in normal control group (46.53 +/- 5.56) pg/ml and astragalus treatment group (41.28 +/- 2.95) pg/ml. CONCLUSIONS: The astragalus could lower the level of hematuria and 24 hours-albuminuria of the IgAN model, and amelioratse the change of the renal pathology and reduce the deposit of IgA in glomerular mesangium. The possible mechanism of the effect is that astragalus could regulate the derangement of Th1, Th2, accordingly could improve the level of IL-4 and IFN-gamma in the serum and diminish the expression of cytokine Th2 TGF-beta1 and IL-5 of the renal tissue, and thereby could postpone the development of IgAN.

[Regulatory effects of yiqi zishen granule on helper T-lymphocyte subsets in IgA nephropathy patients].

OBJECTIVE: To study the pathogenesis of IgA nephropathy (IgAN) and the effect of Yiqi Zishen Granule (YZG) on the helper T-lymphocyte subsets Th1/Th2 in IgAN patients. METHODS: Intracellular cytokines secreted by Th1/Th2 were measured using flow cytometry in 24 healthy subjects and 31 IgAN patients treated by YZG before and after treatment. RESULTS: Level of interferon-gamma (IFN-gamma) was lower (P < 0.05) and levels of interleukin 4 (IL-4) and interleukin 10 (IL-10) were higher (P < 0.01) in the IgAN patients than those in the healthy controls, showing imbalance of Th1/Th2 in the IgAN patients. After YZG treatment, the level of IFN-gamma increased and IL-10 level decreased (P < 0.01). CONCLUSION: Imbalance of Th1/Th2 exists in IgAN patients. YZG has a regulatory effect on imbalance of Th1/Th2 in IgAN patients.

The study of Chinese medicinal herbal formula Shen San Fang in the treatment of experimental IgA nephropathy.

IgA nephropathy (IgAN) is the most common primary glomerulonephritis worldwide, yet there is no effective or specific therapy. Shen San Fang (S3F) is a traditional Chinese herbal medicinal formula that has been used in China for many years to treat patients with hematuria. The aim of this study is to test the therapeutic value of S3F in an experimental model of IgAN. IgAN was induced in Lewis rats by continuous oral immunization with bovine gamma-globulin (BGG) in the drinking water for 8 weeks, followed by intravenous injection of 1 mg BGG daily for 3 successive days. The rats were randomly divided into four groups (five rats/group): control, control receiving S3F, induction of IgAN, and IgAN receiving S3E S3F decoction was fed to rats beginning week 4 from the first day of oral sensitization with BGG. The S3F treatment was continued until the rats were sacrificed or for a 4-week period. Hematuria, renal immunohistochemistry for IgA and transforming growth factor-beta 1 (TGF-beta1), renal histopathology, and renal content of TGF-beta1 were measured. Rats developing IgAN had marked hematuria, profound mesangial proliferation and mesangial expansion, intense and diffuse glomerular IgA deposition, increased glomerular TGF-beta1 expression, and raised renal TGF-beta1 levels. S3F treatment resulted in a significant reduction of hematuria, decreased mesangial IgA deposition, weaker immunostaining of TGF-beta1 in glomerulus, and a lower renal TGF-beta1 concentration. Our animal data suggests a therapeutic value for the Chinese medicinal formula S3F in experimental IgAN. This beneficial effect was due to reduced glomerular IgA deposition and TGF-beta1 expression. Our preliminary findings hold promise for future human therapy.

Deoxynivalenol-induced IgA production and IgA nephropathy-aberrant mucosal immune response with systemic repercussions.

Dietary exposure to the common foodborne mycotoxin deoxynivalenol (DON) selectively upregulates serum immunoglobulin A (IgA) in the mouse, most of which is polymeric, thus suggesting that the mucosal immune system is a primary target. When ingested, DON has no adjuvant or antigen properties but, rather, induces polyclonal IgA synthesis and serum elevation in an isotype-specific fashion. Resultant hyperelevated IgA is polyspecific, autoreactive and is likely to be involved in immune complex formation as well as kidney mesangial deposition. These latter effects mimic IgA nephropathy, the most common human glomerulonephritis. At the cellular level, DON upregulates production of T helper cytokines and enhances T cell help for IgA secretion. Analogous effects are observed in the macrophage with IL-6 being of particular importance based on ex vivo reconstitution and antibody ablation studies as well as experiments with IL-6 deficient mice. Upregulation of cytokines by DON involves both increased transcriptional activation and mRNA stability which are mediated by activation of mitogen-activated protein kinases. Interestingly, dietary omega-3 fatty acids can downregulate these processes and ameliorate DON-induced IgA nephropathy. From the perspective of gut mucosal immunotoxicology, these studies demonstrate that the capacity of a chemical to affect mucosal immune response can have systemic repercussions and, further, that these effects can be modulated by an appropriate nutritional intervention.

Suppressive effects of Perilla frutescens on IgA nephropathy in HIGA mice.

BACKGROUND: Perilla frutescens (perilla) is a herbal medicine used in Japanese traditional Kampo medicine. The present study was conducted to evaluate the anti-nephritic effects of perilla in HIGA mice that spontaneously develop high levels of serum immunoglobulin A (IgA) along with mesangial IgA deposition. METHODS: A perilla decoction and its major active constituent, rosmarinic acid (RsA), were orally administrated to 10-week-old HIGA mice for 16 weeks. At study completion, we measured proteinuria and serum IgA levels and generated histological scores from kidney specimens. In addition, we measured concentrations of IgA in culture media of intestinal Peyer's patch cells and spleen cells obtained from the HIGA mice. RESULTS: Perilla suppressed proteinuria, proliferation of glomerular cells, serum levels of IgA, glomerular IgA and IgG depositions in HIGA mice. Cultured Peyer's patch cells and spleen cells from perilla-treated mice produced significantly less IgA than controls. Rosmarinic acid, by itself, suppressed serum IgA levels and glomerular IgA deposition in HIGA mice. Cultured spleen cells from RsA-treated mice produced less IgA than controls. CONCLUSIONS: The perilla decoction may suppress IgA nephropathy, in part, through modulation of the intestinal mucosal immune system. These effects were caused by RsA acting synergistically with other constituents.

Extrahepatic synthesis of complement proteins in inflammation.

The demonstration of local complement protein synthesis leads to speculation as to the biological significance of this phenomenon. A narrative review is provided to illuminate several queries. It is difficult to establish a causal role for the locally produced complement because participation of systemic complement cannot be excluded. It is also difficult to discern whether local complement synthesis is a beneficial response to an inflammatory event or whether it promotes tissue damage. Finally, it remains to be seen if the roles of local and systemic complement differ in these respects. Extrahepatic expression of complement components of the activation pathways may provide a rapid response to microbial invasion. Once produced and activated, these proteins evoke a phlogistic response composed of cells and soluble mediators of inflammation. Many cells, not only synthesize complement proteins, but can also be stimulated via their complement receptors. This positive feedback may enhance local immune defense, especially in organs isolated from plasma components. In addition, local environmental factors in different organs may differentially regulate complement synthesis. These factors may include pro-inflammatory molecules and non-immune effectors, such as tissue ischemia/reoxygenation and drugs. Local complement dysregulation due to inhibition of activity of a complement regulatory component was shown to cause disease and restoration of the capacity to regulate the complement pathway restored health. Extrahepatic complement synthesis may also modulate local cellular responses, as to decrease detrimental damage of the inflammatory reaction. The demonstration that complement proteins play a significant role in the clearance of apoptotic cells suggests that local synthesis and activation of complement may contribute not only to tissue damage but also to tissue repair.