Antroquinonol differentially modulates T cell activity and reduces interleukin‐18 production, but enhances Nrf2 activation, in murine accelerated severe lupus nephritis

Abstract

Lupus nephritis (LN) is divided into 6 classes based on the severity of the renal histopathologic lesions (1), and histologic transformation between the classes occurs frequently (2,3). Although the exact mechanisms for the histologic transformation of mild mesangial LN into severe renal conditions remain unclear, acute induction of cellular and humoral autoimmunity, including the production of anti-double-stranded DNA (antidsDNA) antibodies (4,5), overexpression of cytokines and chemokines (6,7), differential activation of B cells (8,9), abnormal T cell activation (6,10), and Dnase1 deficiency (11,12), has been implicated. In addition, abundant production of interleukin-12 (IL-12) and IL-18 is seen in the glomeruli of patients and in mouse models of LN, and Th1 cytokines are highly implicated in the development and progression of .IL-18 has also been reported to promote the migration of circulating dendritic cells to the kidney in active LN (15,16). We recently demonstrated that expression of IL-18, induced with lipopolysaccharide

Thrombomodulin domain 1 ameliorates diabetic nephropathy in mice via anti-NF-κB/NLRP3 inflammasome-mediated inflammation, enhancement of NRF2 antioxidant activity and inhibition of apoptosis

“…In the present study, the beneficial effects of THBDD1 on the db/db mice treated suggest that THBD may be protective to diabetes-associated renal damage, although further investigation on this point is warranted. Excessive ROS production has been shown to increase the expression of extracellular matrix proteins involved in the development of renal fibrosis [18], and to play a major pathogenic role in the development and complications of diabetes [8]. Blocking of cellular signalling pathways leading to ROS generation has been shown to blunt DN [34].…”

“…Interestingly, NRF2 has been shown to exert its beneficial effects on DN [29] and other renal conditions [18] by countering oxidative stress. Moreover, the data [18,27] on renal HO-1 in AAV-THBDD1 -treated animals are not consistent with the entirety of the other data in our study, where renal HO-1 levels were greater than in WT mice and vector-alone control db/db mice. This issue needs to be addressed.…”

“…Measurement of ROS production ROS levels in serum and renal tissue were measured as described previously [18]. ROS activity was expressed as relative luminescence units (RLU) per 15 min per mg of organ dry weight, i.e.…”

“…Western blot analysis Rabbit antibodies against mouse NACHT, LRR and PYD domains-containing protein 3 (NLRP3) (Zymed, South San Francisco, CA, USA), caspase-3, caspase-8 or caspase-9 (Cell Signaling Technology, Frankfurt am Main, Germany), and BCL-2 or BAX, as well as goat antibodies against mouse NRF2 or β-actin (Santa Cruz Biotechnology), were used as described previously [18].…”

“…For histopathological evaluation, mesangial expansion (increased matrix), and sclerosis and hyalinosis in the glomerulus, as well as renal interstitial inflammation were evaluated by light microscopy and scored as described previously [18].…”