Echinochrome A Prevents Diabetic Nephropathy by Inhibiting the PKC-Iota Pathway and Enhancing Renal Mitochondrial Function in db/db Mice

Abstract

Echinochrome A (EchA) is a natural bioproduct extracted from sea urchins, and is an active component of the clinical drug, Histochrome®. EchA has antioxidant, anti-inflammatory, and antimicrobial effects. However, its effects on diabetic nephropathy (DN) remain poorly understood. In the present study, seven-week-old diabetic and obese db/db mice were injected with Histochrome (0.3 mL/kg/day; EchA equivalent of 3 mg/kg/day) intraperitoneally for 12 weeks, while db/db control mice and wild-type (WT) mice received an equal amount of sterile 0.9% saline. EchA improved glucose tolerance and reduced blood urea nitrogen (BUN) and serum creatinine levels but did not affect body weight. In addition, EchA decreased renal malondialdehyde (MDA) and lipid hydroperoxide levels, and increased ATP production. Histologically, EchA treatment ameliorated renal fibrosis. Mechanistically, EchA suppressed oxidative stress and fibrosis by inhibiting protein kinase C-iota (PKCι)/p38 mitogen-activated protein kinase (MAPK), downregulating p53 and c-Jun phosphorylation, attenuating NADPH oxidase 4 (NOX4), and transforming growth factor-beta 1 (TGFβ1) signaling. Moreover, EchA enhanced AMPK phosphorylation and nuclear factor erythroid-2-related factor 2 (NRF2)/heme oxygenase 1 (HO-1) signaling, improving mitochondrial function and antioxidant activity. Collectively, these findings demonstrate that EchA prevents DN by inhibiting PKCι/p38 MAPK and upregulating the AMPKα/NRF2/HO-1 signaling pathways in db/db mice, and may provide a therapeutic option for DN.

Multi‐omic analysis reveals genes and proteins integral to bioactivity of Echinochrome A isolated from the waste stream of the sea urchin industry in Aotearoa New Zealand

“…Ech A has exhibited in vitro and in vivo bioactivity in multiple tissues including kidney (Cui et al, 2022), skin (Choi et al, 2022;Kim et al, 2023;Seol et al, 2021;Yun et al, 2021), heart (Artyukov et al, 2020;Jeong, Kim, Song, Lee, et al, 2014;Kim et al, 2015;Song et al, 2022;Tang et al, 2023), bone (Hou et al, 2020), lung (Lebed'ko et al, 2015;Seo et al, 2015) and eyes (Lennikov et al, 2014). These results may help explain the therapeutic efficacy of Ech A, perhaps via the antioxidant, anti-inflammatory and metal-chelating activities, against several common ailments and diseases (e.g., diabetes (Mohamed et al, 2016;Pham et al, 2023), ischemia/stroke (Kim et al, 2019;Sedova et al, 2015), viral infections (Fedoreyev et al, 2018;Mishchenko et al, 2020), bacterial infections (Sadek et al, 2021), inflammation (Park et al, 2021;Rubilar et al, 2021;Sadek et al, 2021), cancer (Lazarev et al, 2016;Mohamed, 2021) and neurodegenerative diseases (Ekimova et al, 2018;Lee, Pronto, et al, 2014)). As only genes involved in these bioactivities have been investigated (e.g., GSH and SOD genes to explain antioxidant bioactivity; ERK and p53 genes to explain cell survival signaling bioactivity), The genes and pathways mediating these bioactivities are not fully understood.…”

Algae-Derived Natural Products in Diabetes and Its Complications—Current Advances and Future Prospects

“…Algae-derived compounds, with their antioxidant and anti-inflammatory properties, have shown potential for protecting retinal cells and preventing the progression of retinopathy [ 35 , 36 ]. Similarly, algae-derived compounds have demonstrated reno-protective effects by reducing albuminuria, attenuating renal fibrosis, and modulating the inflammatory pathways, providing a potential avenue for managing diabetic nephropathy [ 37 , 38 ].…”