Nitro-oleic acid inhibits the high glucose-induced epithelial-mesenchymal transition in peritoneal mesothelial cells and attenuates peritoneal fibrosis

Abstract

As an electrophilic nitroalkene fatty acid, nitro-oleic acid (OA-NO2) exerts multiple biological effects that contribute to anti-inflammation, anti-oxidative stress, and antiapoptosis. However, little is known about the role of OA-NO2 in peritoneal fibrosis. Thus, in the present study, we examined the effects of OA-NO2 on the high glucose (HG)-induced epithelial-mesenchymal transition (EMT) in human peritoneal mesothelial cells (HPMCs) and evaluated the morphological and immunohistochemical changes in a rat model of peritoneal dialysis-related peritoneal fibrosis. In in vitro experiments, we found that HG reduced the expression level of E-cadherin and increased Snail, N-cadherin, and α-smooth muscle actin expression levels in HPMCs. The above-mentioned changes were attenuated by pretreatment with OA-NO2. Additionally, OA-NO2 also inhibited HG-induced activation of the transforming growth factor-β1/Smad signaling pathway and NF-κB signaling pathway. Meanwhile, OA-NO2 inhibited HG-induced phosphorylation of Erk and JNK. The results from the in vivo experiments showed that OA-NO2 notably relieved peritoneal fibrosis by decreasing the thickness of the peritoneum; it also inhibited expression of transforming growth factor-β1, α-smooth muscle actin, N-cadherin, and vimentin and enhanced expression of E-cadherin in the peritoneum. Collectively, these results suggest that OA-NO2 inhibits the HG-induced epithelial-mesenchymal transition in HPMCs and attenuates peritoneal dialysis-related peritoneal fibrosis.

Nitroalkene fatty acids modulate bile acid metabolism and lung function in obese asthma

“…CXA-10 (P.O., daily, 2 wk) activated multiple tissue defense mechanisms and inhibited pro-inflammatory signaling responses. These basic research and clinical studies have produced reproducible data that has culminated into a profile of targets in various disease pathologies that include a) the inhibition of NF-kB-regulated inflammatory cytokine, adipokine (leptin and adiponectin) and adhesion molecule expression 20 , 33 , 34 , b) the inhibition of pro-inflammatory macrophage activation 35 , 36 , c) the activation of Nrf2-regulated adaptive gene expression 37 , 38 and d) the prevention and reversal of fibrosis 19 , 36 , 39 , 40 . Based on this data, a clinical trial administering CXA-10 for 6 weeks is ongoing in obesity-associated asthma (NCT03762395).…”

Fatty acid nitroalkene reversal of established lung fibrosis

“…These structurally dissimilar electrophiles all limit the progression of fibrosis in multiple models of tissue injury that variously involve metabolic stress, inflammation and fibrotic responses ( Table 2 ). Importantly, the two FDA-approved drugs specified for the treatment of fibrosis, nintendanib and pirfenidone, are both α,β-unsaturated carbonyl-containing small molecule electrophiles and share mechanisms of pathway modulation in common with other small molecule electrophiles [ 16 , 25 , 31 , 32 , [76] , [77] , [78] , [79] , [80] , [81] , [82] , [83] , [84] , [85] , [86] , [87] , [88] , [89] , [90] , [91] , [92] , [93] , [94] , [95] , [96] , [97] , [98] , [99] , [100] , [101] , [102] , [103] , [104] ].…”

“…These pro-inflammatory signaling actions induce the expression of α-SMA in vimentin positive FB [ 135 ], with the combination of these two markers serving as an index of myoFB quantity and differentiation state [ 136 ]. NFκB signaling, inhibited by NO 2 -OA binding to critical p50 and p65 subunit cysteines, limits pro-inflammatory mediator expression in multiple cell systems [ 26 , 32 , 72 , 94 , 95 , 121 , 137 , 138 ]. Numbers of myoFB were decreased by NO 2 -OA in PCLS from both control and bleomycin-treated mice, with the population of vimentin positive cells not altered ( Fig.…”

“…One can anticipate that a highly specific immunomodulatory approach will have limited effects, since it is necessary to target diverse cell populations to not only mitigate, but also reverse fibrotic responses. Notably, NO 2 -OA and other small molecule electrophiles show promising pleiotropic immunomodulatory potential [ 26 , 32 , 72 , 73 , 93 , 95 , 120 , 121 , 124 , 125 , 127 , 129 , 137 , 138 ].…”

Nitro-Oleic Acid (NO2-OA) Improves Systolic Function in Dilated Cardiomyopathy by Attenuating Myocardial Fibrosis

“…Smad-independent non-canonical TGFβ signaling includes the activation of Mitogen-activated kinases (MAPK) such as Erk1/2 [38,39]. NO 2 -OA suppresses phosphorylation of Erk1/2 in various cell types, including vascular smooth muscle cells in pulmonary hypertension, and peritoneal mesenchymal cells in a murine model of dialysis-related peritoneal damage [40,41]. Consequently, NO 2 -OA treatment prevented fibrotic remodeling in the right ventricle and the peritoneum, respectively.…”