Pham TK et al. (2023), Echinochrome A Prevents Diabetic Nephropathy by...

ECB-ART-51458

Mar Drugs 2023 Mar 30;214:. doi: 10.3390/md21040222.

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

Pham TK , Nguyen THT , Yun HR , Vasileva EA , Mishchenko NP , Fedoreyev SA , Stonik VA , Vu TT , Nguyen HQ , Cho SW , Kim HK , Han J .

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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.

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	Figure 6. Schematic diagram depicting the potential renal-protective mechanism of EchA in diabetic nephropathy.
	Figure 1. Effect of EchA on body weight, blood glucose, blood urea nitrogen (BUN), creatinine, and insulin levels in db/db mice. (A) Morphology of the WT, db/db, and db/db + EchA mice at 19 weeks old and after 12 weeks of treatment. (B) Body weight. (C) Fasting blood glucose. (D) BUN levels. (E) Serum creatinine levels. (F) Glucose tolerance. (G) Insulin levels. Data are presented as mean ± SEM; * p < 0.05, p < 0.01, ** p < 0.0001; # p < 0.05, ### p < 0.001, #### p < 0.0001 in the WT vs. the db/db and db/db + EchA groups. ϯ p < 0.05, ϯϯϯ p < 0.001 in the db/db vs. the db/db + EchA groups (n = 6/group).
	Figure 2. Effects of EchA treatment on renal hypertrophy and fibrosis in db/db mice. (A) Representative images of whole kidneys from mice in the different treatment groups. (B) The ratio of kidney weight to tibia length of the mice. (C) Representative images of HE- and MT-stained kidney sections. Magnification, 400×. The scale bar represents 100 μm. (D) Glomerulus volume proportion based on HE staining. (E) Renal interstitial fibrosis area based on MT staining. (F) Immunoblot analysis of protein expression related to renal fibrosis. (G–J) Quantitative analysis of transforming growth factor-beta 1 (TGF-β1), collagen III (Col3), alpha smooth muscle actin (αSMA), phospho-suppressor of mothers against decapentaplegic 2 (p-SMAD2), total SMAD2, and β-actin in the kidneys of mice, as determined via Western blotting. Data are presented as mean ± SEM. * p < 0.05, p < 0.01, * p < 0.001 (n = 6/group).
	Figure 3. Effects of EchA treatment on oxidative stress in the renal tissue of db/db mice. (A) Renal malondialdehyde (MDA) levels. (B) Renal lipid hydroperoxide levels. (C) Immunoblot analysis of the expression of proteins related to oxidative stress in renal tissues. (D–G) Quantitative analysis of NADPH oxidase 2 (NOX2), NOX4, superoxide dismutase 1 (SOD1), SOD2, and β-actin protein expression levels in the kidneys of mice, as determined using Western blotting. Data are presented as mean ± SEM. * p < 0.05, p < 0.01, ** p < 0.0001 (n = 6/group).
	Figure 4. EchA regulates high-glucose-induced p-AMPK, PGC-1α, and NRF2/HO-1 expression and activates ATP production in diabetic kidneys. (A) Renal ATP levels. (B) Immunoblot analysis of the protein expression of AMP-activated protein kinase (AMPK) in the total and phosphorylated form, peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), nuclear factor erythroid-2-related factor 2 (NRF2), heme oxygenase-1 (HO-1), and β-actin. (C–F) Statistical analysis of the expression of these proteins mentioned in (B). Data are presented as mean ± SEM. * p < 0.05, ** p < 0.01 (n = 6/group).
	Figure 5. Effect of EchA treatment on PKCι expression and the phosphorylation p53 and c-Jun in the kidney tissues of db/db mice. (A) Analysis of the protein expression of PKCι, p-p38 MAPK, p38 MAPK, and β-actin using Western blot analysis. (B) Quantitative analysis of PKCι protein expression. (C) mRNA expression of PKCι in the kidney as determined using real-time PCR. (D) Quantitative analysis of p-p38 MAPK phosphorylation. (E) Immunoblot analysis of the protein expression of p-p53, p53, p-c-Jun, c-Jun, and β-actin. (F,G) Statistical analysis of the expression of the examined proteins. Data are presented as mean ± SEM. * p < 0.05, ** p < 0.01 (n = 6/group).

References [+] :

Afkarian, Kidney disease and increased mortality risk in type 2 diabetes. 2013, Pubmed