Renoprotective effects of xenon on lupus nephritis by inhibiting NLRP3 inflammasome and oxidative stress Shuk-Man Ka, PhD Associate Professor Academy of Medicine, National Defense Medical Center, Taipei, Taiwan Orlando USA Sep 29 2016

Accelerated and severe lupus nephritis Accelerated and severe lupus nephritis (ASLN) features acute onset of severe clinical manifestations and histopathological renal lesions, may represent a severe form of renal inflammation and fibrosis, with relatively high possibility of progressing to uremia and the patients require dialysis treatment or renal transplantation. (A representative case from Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan)

WHO classification of lupus nephritis

Current treatment for ASLN . Current treatment for ASLN The current therapy for ASLN is to the mainly use corticosteroids or combined corticosteroids with other cytotoxic agents or immunomodulators (such as cyclophosphamide, azathioprine or cyclosporine), although many of them are found to have severe systemic side effects. Cyclosphosphamide Chlorambucil Mycophenolate mofetil NSAIDs ACE inhibitors Molino C et al., Eur J Intern Med, 20: 447-453, 2009; Yee CS et al., Ann Rheum Dis, 63: 525-529, 2004; Benseler SM et al., Rheumatology (Oxford), 48: 176-182, 2009.

Xenon (Xe) Xe is a colorless, dense, odorless noble gas found in the Earth's atmosphere in trace amounts. Xe triggers pro-inflammatory effects and suppresses the anti- inflammatory response compared to sevoflurane in patients undergoing cardiac surgery. Xe has been described as a renaprotectant in models of renal transplantation and acute kidney. Mervyn Maze and MBChB, Can J Anesth, 2015 Breuer et al., Critical Care ,2015

Albuminuria and renal function

Renal pathology Control ASLN ASLN+ Xe

Renal T cell and macrophage infiltration Control ASLN ASLN+ Xe F4/80 CD3

Renal dendritic cells infiltration Control ASLN ASLN+ Xe DCs CD11b

Serum proinflammatory cytokines

Renal and urinary ROS Renal HO-1 (ng/ml) Renal Nrf2 activity In situ renal ROS ** * Kidney superoxide anion (RLU/15 min/mg) Control ASLN ASLN+Xe * * * ** Renal Nrf2 activity Renal HO-1 (ng/ml) (OD/mg nuclear protein) Control ASLN ASLN+Xe Control ASLN ASLN+Xe

Renal NF-kB signal pathway p-NF-κB p65 ICAM-1 β-actin ** * Renal p-NF-kB activity (OD/mg protein) Control ASLN ASLN+Xe

NF-kB signal pathways in primary mesangial cells Xe - - - - + + + LPS (mins) 0 30 60 360 30 60 360 ICAM-1 p-p-38 β-actin p-NF-κB p65 Lamin A

Renal apoptosis (A) BAX Bcl-2

Mitochondria injury in primary mesangial cells (B) * * Xe - - + + LPS - + - + (C) R2: 93.07% R3: 4.68% R2: 87.45% R3: 9.31% R2: 93.22% Con LPS+ATP LPS+ATP+Xe  

Conclusion Xe inhibited the development of ASLN, as demonstrated by reduced albuminuria, improved renal function, and improved renal histopathology. Mechanistic studies showed that inhibition of the activation of NF-kB/NLRP3 inflammasome pathways and apoptosis-related signal pathways, and antioxidant signaling were involved in the major mechanisms of action for the renoprotective effects of Xe.

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