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Using honokiol (HNK), a major anti-inflammatory bioactive compound in Magnolia officinalis, we show a potent therapeutic outcome against an accelerated, severe form of lupus nephritis (ASLN). The latter may follow infectious insults that act as environmental triggers in the patients. In the current study, an ASLN model in NZB/W F1 mice was treated with HNK by daily gavage after onset of the disease. We show that HNK ameliorated the ASLN by improving renal function, albuminuria, and renal pathology, especially reducing cellular crescents, neutrophil influx, fibrinoid necrosis in glomeruli, and glomerulonephritis activity scores. Meanwhile, HNK differentially regulated T cell functions, reduced serum anti-dsDNA autoantibodies, and inhibited NLRP3 inflammasome activation in the mice. The latter involved: (a) suppressed production of reactive oxygen species and NF-κB activation-mediated priming signal of the inflammasome, (b) reduced mitochondrial damage, and (c) enhanced sirtuin 1 (SIRT1)/autophagy axis activation. In conclusion, HNK represents a new drug candidate for acute, severe episodes of LN capable of alleviating renal lesions in ASLN mice by negatively regulating T cell functions and by enhancing SIRT1/autophagy axis-lessened NLRP3 inflammasome activation.

Xenon, an inert anesthetic gas, is increasingly recognized to possess desirable properties including cytoprotective and anti-inflammatory effects. Here we evaluated the effects of xenon on the progression of lupus nephritis (LN) in a mouse model. A two hour exposure of either 70% xenon or 70% nitrogen balanced with oxygen was administered daily for five weeks to female NZB/W F1 mice that had been induced to develop accelerated and severe LN. Xenon treatment improved kidney function and renal histology, and decreased the renal expression of neutrophil chemoattractants, thereby attenuating glomerular neutrophil infiltration. The effects of xenon were mediated primarily by deceasing serum levels of anti-double stranded DNA autoantibody, inhibiting reactive oxygen species production, NF-κB/NLRP3 inflammasome activation, ICAM-1 expression, glomerular deposition of IgG and C3 and apoptosis, in the kidney; and enhancing renal hypoxia inducible factor 1-α expression. Proteomic analysis revealed that the treatment with xenon downregulated renal NLRP3 inflammasome-mediated cellular signaling. Similarly, xenon was effective in improving renal pathology and function in a spontaneous LN model in female NZB/W F1 mice. Thus, xenon may have a therapeutic role in treating LN but further studies are warranted to determine applicability to patients.

Background Renal tubulointerstitial lesions (TILs), a key pathological hallmark for chronic kidney disease to progress to end-stage renal disease, feature renal tubular atrophy, interstitial mononuclear leukocyte infiltration and fibrosis in the kidney. Our study tested the renoprotective and therapeutic effects of compound K (CK), as described in our US patent (US7932057B2), on renal TILs using a mouse unilateral ureteral obstruction (UUO) model. Methods Renal pathology was performed and renal draining lymph nodes were subjected to flow cytometry analysis. Mechanism-based experiments included the analysis of mitochondrial dysfunction, a model of tubular epithelial cells (TECs) under mechanically induced constant pressure (MICP) and tandem mass tags (TMT)-based proteomics analysis. Results Administration of CK ameliorated renal TILs by reducing urine levels of proinflammatory cytokines, and preventing mononuclear leukocyte infiltration and fibrosis in the kidney. The beneficial effects clearly correlated with its inhibition of: (i) NF-κB-associated priming and the mitochondria-associated activating signals of the NLRP3 inflammasome; (ii) STAT3 signalling, which in part prevents NLRP3 inflammasome activation; and (iii) the TGF-β-dependent Smad2/Smad3 fibrotic pathway, in renal tissues, renal TECs under MICP and/or activated macrophages, the latter as a major inflammatory player contributing to renal TILs. Meanwhile, TMT-based proteomics analysis revealed downregulated renal NLRP3 inflammasome activation-associated signalling pathways in CK-treated UUO mice. Conclusions The present study, for the first time, presents the potent renoprotective and therapeutic effects of CK on renal TILs by targeting the NLRP3 inflammasome and STAT3 signalling.

The NLRP3 inflammasome is a caspase-1-containing multi-protein complex that controls the release of IL-1β and plays important roles in the development of inflammatory disease. Here, we report that resveratrol, a polyphenolic compound naturally produced by plants, inhibits NLRP3 inflammasome-derived IL-1β secretion and pyroptosis in macrophages. Resveratrol inhibits the activation step of the NLRP3 inflammasome by suppressing mitochondrial damage. Resveratrol also induces autophagy by activating p38, and macrophages treated with an autophagy inhibitor are resistant to the suppressive effects of resveratrol. In addition, resveratrol administration mitigates glomerular proliferation, glomerular sclerosis, and glomerular inflammation in a mouse model of progressive IgA nephropathy. These findings were associated with decreased renal mononuclear leukocyte infiltration, reduced renal superoxide anion levels, and inhibited renal NLRP3 inflammasome activation. Our data indicate that resveratrol suppresses NLRP3 inflammasome activation by preserving mitochondrial integrity and by augmenting autophagy.