SGLT-2 Inhibitors and the Inflammasome: What’s Next in the 21st Century?

Abstract

The nucleotide-binding domain-like receptor protein 3 (NLRP3) inflammasome in the kidney and the heart is increasingly being suggested to play a key role in mediating inflammation. In the kidney, NLRP3 activation was associated with the progression of diabetic kidney disease. In the heart, activation of the NLRP3 inflammasome was related to the enhanced release of interleukin-1β (IL-1β) and the subsequent induction of atherosclerosis and heart failure. Apart from their glucose-lowering effects, SGLT-2 inhibitors were documented to attenuate activation of the NLRP3, thus resulting in the constellation of an anti-inflammatory milieu. In this review, we focus on the interplay between SGLT-2 inhibitors and the inflammasome in the kidney, the heart and the neurons in the context of diabetes mellitus and its complications.

Knockdown of lncRNA MALAT1 attenuates renal interstitial fibrosis through miR-124-3p/ITGB1 axis

“…High glucose induced the production of multiple proinflammatory cytokines (e.g., IL-1, IL-6, and TNF-α), ECM proteins 42 , autophagic flux in HK2 cells 43 . High www.nature.com/scientificreports/ glucose often plays a key role in the development of diabetic nephropathy, and a growing body of evidence suggests that dysregulation of NLRP3 activation may play a role in the progress of diabetic nephropathy via regulation of inflammatory response and RIF 44,45 . As a renal growth factor, angiotensin (Ang) II could also increases proinflammatory process and regulates matrix degradation in RIF 46,47 .…”

The Interplay Between Dietary Choline and Cardiometabolic Disorders: A Review of Current Evidence

“…Activation of NLRP3 is achieved by a transformational change in the structure of NLRP3, which is attributed to the activation of caspase-1 from procaspase. In turn, the activated NLRP3 results in the release of various pro-inflammatory cytokines, especially interleukin (IL) 1β and IL-18 [ 41 , 42 ]. This vicious cycle accounts for the development of inflammation seen in NASH, whereas the release of tumor growth factor β (TGF-β) is responsible for collagen deposition and the progression of NAFLD to cirrhosis [ 43 , 44 ].…”

NAFLD in the 21st Century: Current Knowledge Regarding Its Pathogenesis, Diagnosis and Therapeutics

“…This increase in unfolded proteins activates a cascade widely known as the unfolded protein response (UPR). Despite the fact that UPR is activated to promote homeostasis, chronic ER stress may induce the UPR cascade, which, in turn, may lead to severe inflammation, the production of reactive oxygen species (ROS), and, finally, cell death [18][19][20][21][22][23][24][25]. Figure 1 depicts the involvement of UPR in ER stress and inflammation.…”

“…In addition, ROS binds to nucleotide-binding domain-like receptor protein 3 (NLRP3), an inflammasome that, when activated by the canonical inflammasome pathway, i.e., via pro-caspase-1, results in the production of caspase-1. Caspase-1 leads to transformational alterations in NLRP3, which provoke the production of the pro-inflammatory cytokines IL-18 (interleukin-18) and IL-1β (interleukin-1β) [18][19][20][21][22][23][24][25]. This vicious cycle accounts for the inflammation seen in NASH.…”