Induction of Autophagy by Pterostilbene Contributes to the Prevention of Renal Fibrosis via Attenuating NLRP3 Inflammasome Activation and Epithelial-Mesenchymal Transition

Abstract

Chronic kidney disease (CKD) is recognized as a global public health problem. NLRP3 inflammasome activation has been characterized to mediate diverse aspect mechanisms of CKD through regulation of proinflammatory cytokines, tubulointerstitial injury, glomerular diseases, renal inflammation, and fibrosis pathways. Autophagy is a characterized negative regulation mechanism in the regulation of the NLRP3 inflammasome, which is now recognized as the key regulator in the pathogenesis of inflammation and fibrosis in CKD. Thus, autophagy is undoubtedly an attractive target for developing new renal protective treatments of kidney disease via its potential effects in regulation of inflammasome. However, there is no clinical useful agent targeting the autophagy pathway for patients with renal diseases. Pterostilbene (PT, trans-3,5-dimethoxy-4-hydroxystilbene) is a natural analog of resveratrol that has various health benefits including autophagy inducing effects. Accordingly, we aim to investigate underlying mechanisms of preventive and therapeutic effects of PT by reducing NLRP3 inflammasome activation and fibrosis through autophagy-inducing effects. The renal protective effects of PT were evaluated by potassium oxonate (PO)-induced hyperuricemia and high adenine diet-induced CKD models. The autophagy induction mechanisms and anti-fibrosis effects of PT by down-regulation of NLRP3 inflammasome are investigated by using immortalized rat kidney proximal tubular epithelial NRK-52E cells. To determine the role of autophagy induction in the alleviating of NLRP3

Review on Inflammation Markers in Chronic Kidney Disease

“…Additionally, NLRP3 inhibition could attenuate obesity-related kidney disease [ 52 ]. A novel agent pterostilbene , an analog of resveratrol with autophagy-inducing effects, has shown its renal protective effects in an invitro study of urate nephropathy by down-regulating the NLRP3 inflammasome [ 53 ].…”

Natural Products that Target the NLRP3 Inflammasome to Treat Fibrosis

“…Resveratrol, the most widely studied stilbene, possesses the ability to attenuate particulate matter (PM 2.5 )-induced cytotoxity in PM 2.5 -treated BEAS-2B cells via inhibiting autophagy, which is an evolutionarily conserved cellular process facilitating the clearance of NLRP3 activators such as β-amyloid and damaged mitochondria, thus suppressing the NLRP3 inflammasome activation (Nakahira et al, 2011;Cho et al, 2014). Pterostilbene, a dimethylated analog of resveratrol, can also markedly augment autophagy to inhibit NLRP3 inflammasome activation, thereby reducing the TGF-β triggered expression of EMT markers including E-cadherin, fibronectin and α-SMA in immortalized rat kidney proximal tubular epithelial cells (NRK-52E cells) (Wang et al, 2020d). Polydatin, a resveratrol glucoside, is able to decrease the expression of a-SMA, collagen Ⅰ, and Ⅲ in human lung epithelial BEAS-2B cells, however, the inhibitory effect of which can be reversed by overexpression of NLRP3.…”

“…The stilbenes also improve organ fibrosis in vivo. In models of potassium oxonate (PO)-induced hyperuricemia and high adenine diet (HAD)-induced chronic kidney disease (CKD), pterostilbene-triggered autophagy has an attenuating effect on the improvement of renal function and interstitial fibrosis via restraining EMT-mediated NLRP3 inflammasome activation (Wang et al, 2020d). Resveratrol is effective at alleviating lung inflammation and fibrosis caused by particulate matter (PM 2.5 ) via inhibiting autophagy-related NLRP3 inflammasome activation in BALB/c mice (Ding et al, 2019).…”

Modulation of Innate Immune Toxicity by Silver Nanoparticle Exposure and the Preventive Effects of Pterostilbene

“…In this regard, pterostilbene (PTE, trans-3,5-dimethoxy-4-hydroxystilbene), a naturally occurring analog of resveratrol and is a stilbene compound with many health benefits, was used in the study. The protective effects of PTE include its antioxidant activity, anti-inflammatory effects, anti-obesity, and chemopreventive effects, which are attributed to its unique structure [ 13 , 14 , 15 ]. Current studies also indicated the modulation effects of PTE on the immune response.…”