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

Echinochrome A (EchA) is a natural bioproduct extracted from sea urchins, and is an active component of the clinical drug, Histochrome((R)). 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 (PKC iota)/p38 mitogen-activated protein kinase (MAPK), downregulating p53 and c-Jun phosphorylation, attenuating NADPH oxidase 4 (NOX4), and transforming growth factor-beta 1 (TGF beta 1) signaling. Moreover, EchA enhanced AMPK phosphorylation and nuclear factor erythroid2-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 PKC iota/p38 MAPK and upregulating the AMPK alpha/NRF2/HO-1 signaling pathways in db/db mice, and may provide a therapeutic option for DN.

Automated summary

Echinochrome A (EchA), a natural bioproduct from sea urchins, has antioxidant, anti-inflammatory, and antimicrobial effects. This study investigated its effects on diabetic nephropathy (DN) using mouse models. The results showed that EchA improved glucose tolerance, reduced biomarkers of kidney damage, decreased oxidative stress, and ameliorated renal fibrosis. Mechanistically, EchA inhibited specific signaling pathways involved in oxidative stress and fibrosis, while enhancing mitochondrial function and antioxidant activity. These findings suggest that EchA may be a therapeutic option for DN.