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Activating Nrf-2 Signaling by Sulforaphane Attenuates Unilateral Ureteral ObstructionEnhanced Apoptosis and Pyroptosis in Kidney 林威佑、戴槐青、鄭劍廷1、余宏政 台灣大學醫學院附設醫院 泌尿部 1國立臺灣師範大學生命科學系 Introduction Clinically, ureteral obstruction is a common problem. Incidence: 3.9% Cause: ○ Ureteral stone ○ Benign prostate hyperplasia ○ Urothelial tumor ○ Other causes such as ureteral stricture Hegarty et al., 2001 Increased reactive oxygen species (ROS) may promote two types of programmed cell death in the obstructed kidney apoptosis and pyroptosis Sulforaphane (SA) via activating Nrf-2 antioxidant signaling may protect UUOinduced renal damage Method Unilateral ureteral obstruction (UUO) A well animal model of mimic renal injury leading to interstitial fibrosis Nagatoya et al., 2002 Left kidney of Female Wistar rats Normal UUO UUO and sulforaphane UUO Normal N=3 UUO N=3 UUO and SA N=3 Immunohistochemisty and Western blot Reactive oxygen species (ROS) Fibrosis, ED-1 (macrophage/monocyte) infiltration, oxidative stress, autophagy, apoptosis and pyroptosis Result H.E.Stain Normal UUO 7day SA UUO 7day ED1 Stain Macrophage Normal UUO 7day SA UUO 7day 4HNE Stain Lipid Oxide Normal UUO 7day SA UUO7day Beclin Stain Autophagy Normal Normal UUO 7day UUO & SA 7day Beclin 1 β-actin 1.2 UUO 7day * 1.0 0.8 0.6 0.4 SA UUO 7day 0.2 0.0 control UUO UUO+SA 偵測腎臟組織細胞自噬初期蛋白Beclin-1表現，觀察時間 點為Normal、阻塞七天、阻塞七天+DL-蘿蔔硫素(n=3)。 ＊表示與Normal組有顯著差異(p<0.05)。 N Engl J Med 2012 ATG5-ATG12 Stain Autophagy Normal Normal UUO 7day UUO & SA 7day Atg5-Atg12 β-actin 1.2 * 1.0 UUO 7day 0.8 0.6 0.4 0.2 SA UUO 7day 0.0 control UUO UUO+SA 偵測腎臟組織細胞自噬過程促自噬泡形成之Atg5-Atg12蛋 白表現，觀察時間點為Normal、阻塞七天、阻塞七天+ DL-蘿蔔硫素(n=3)。 ＊表示與Normal組有顯著差異(p<0.05)。 N Engl J Med 2012 LC3II Stain Autophagy Normal UUO 7day UUO & SA 7day LC3II Normal β-actin 1.2 * 1.0 0.8 UUO 7day 0.6 0.4 0.2 SA UUO 7day 0.0 control UUO UUO+SA 偵測腎臟組織細胞自噬之自噬泡形成代表性蛋白LC3 typeⅡ 表現，觀察時間點為Normal、阻塞七天、阻塞七天+ DL-蘿 蔔硫素(n=3)。 ＊表示與Normal組有顯著差異(p<0.05)。 N Engl J Med 2012 Caspase1 Stain pyropotosis IL1-βStain pyropotosis Normal Normal UUO 7day UUO 7day SA UUO 7day SA UUO 7day Nrf2 Stain Normal UUO 7day UUO & SA 7day Nrf2 Normal β-actin 1.2 * 1.0 0.8 UUO 7day 0.6 0.4 0.2 SA UUO 7day 0.0 control UUO UUO+SA 偵測腎臟組織細胞自噬過程Nrf2蛋白表現，觀察時間 點為Normal、阻塞七天、阻塞七天+ DL-蘿蔔硫素 (n=3)。 ＊表示與control組有顯著差異(p<0.05)。 sulforaphane UOO Nuclear Nrf-2 translocation Cytosolic Nrf-2 Cytosolic Bax translocation to mitochondria MOMP Enhance mitochondrial Cytochrome c release into the cytosol Cytochrome C Stain Control UUO 7day SA UUO7day Masson Stain Hydroxylproline Normal UUO 7day Hydroxylproline concent (mg/ml) 100 SA UUO7day Normal n=3 UUO7days UUO7days&SA 80 * 60 40 * 20 0 Normal UUO7days UUO7&SA days Conclusion Conclusion: Sulforaphane via activating Nrf-2 signaling to preserve mitochondrial function and suppressed UUO-induced renal apoptosis and pyroptosis Thank you for your attention!!