Nephrotic syndrome (NS) is a clinical syndrome with various causes that are caused by excessive excretion of protein, typically resulting in the accumulation of fluid in the body (edema), along with decreased blood levels of a protein called albumin and increased blood levels of lipids. It is primarily characterized by severe proteinuria, hypoalbuminemia, and edema. Currently, identifying effective and less toxic therapeutic interventions for NS remains a significant problem.
In this blog, I would like to introduce the study, “Comparative Study of Fucoidan from Saccharina japonica and Its Depolymerized Fragment on Adriamycin-Induced Nephrotic Syndrome in Rats” by Jiaojiao Tan et al.
First, fucoidan was isolated from Saccharina japonica and its depolymerized fragments which are low molecular weight fucoidan (LMWF) by oxidative decomposition using a combination of hydrogen peroxide and ascorbic acid were prepared by oxidative degradation. Fucoidan and its depolymerized fragments had similar chemical compositions and average molecular weights of 136 kDa and 9.5 kDa, respectively. Adriamycin-induced nephrotic syndrome is a typical nephrotic syndrome model. So, they observed the general condition of the animals during the experiment. Compared with normal rats, rats administered Adriamycin showed abnormal behaviors such as decreased food intake, fatigue, weakness, discoloration, and hair loss. Some animals showed obvious diarrhea.
Proteinuria is the most important feature of nephrotic syndrome. Rats were collected for 24-hour urine once a week to measure urinary protein concentration. The 24-hour urinary protein excretion of all rats was detected. Two weeks after Adriamycin administration, the 24-hour urinary protein of the model group was significantly higher than that of the normal group and increased over time. The urinary protein excretion of rats treated with fucoidan or LMWF (50 or 100 mg/kg) was significantly reduced after administration and was significantly different from the urinary protein excretion of the model rats. The results suggested that both fucoidan and LMWF could improve the symptoms of hyperalbuminemia and gradually restore the damage of the glomerular filtration membrane caused by Adriamycin. Compared with fucoidan, LMWF at a dose of 100 mg/kg had significantly lower urinary protein excretion, suggesting that low molecular weight fucoidan can inhibit the production of proteinuria with higher activity.
At the end of the experiment, the blood biochemical indicators of the rats were detected. The blood concentrations of total protein (TP), albumin, blood urea nitrogen (BUN), serum creatinine (SCr), total cholesterol (TC), and total triglyceride (TG) in the model rats were significantly changed. Compared with normal rats, the blood concentrations of total cholesterol and total triglyceride in the model rats induced by Adriamycin increased by 9.4 and 6.4 times, respectively. These results indicated that Adriamycin treatment could induce significant hyperlipidemia.
Blood urea nitrogen and serum creatinine are two major indicators of renal function. Rats administered Adriamycin had higher BUN and SCr levels, indicating that the kidneys of the model rats were damaged by Adriamycin administration, and the blood total protein and albumin levels of the model rats were decreased by Adriamycin, suggesting that hypoalbuminemia occurred in the model rats. However, the changes in these biochemical indicators could be significantly reversed by the administration of fucoidan and LMWF in a dose-dependent manner. Fucoidan, dexamethasone, and LMWF (50 mg/kg) reduced the levels of BUN and SCr to a similar extent. Both fucoidan and LMWF could significantly increase blood albumin concentration and reduce TG and TC concentrations, and LMWF at a dose of 100 mg/kg showed more potent activity. These results indicated that both fucoidan and its depolymerized fragments could improve renal function, increase blood albumin concentration, and suppress hyperlipidemia. Low molecular weight fucoidan showed more potent activity.
When Adriamycin is converted into semiquinone free radicals in vivo, the radicals react with oxygen to generate reactive oxygen species (ROS). ROS further induces lipid peroxidation in glomerular epithelial cells, destroys the structure and function of the filtration membrane, and causes proteinuria and subsequent nephrotic syndrome.
Fucoidan and low molecular weight fucoidan have been proven to have free radical scavenging activity in vitro. The antioxidant activity of fucoidan can help remove reactive oxygen species caused by Adriamycin and maintain the structure and function of the glomerular basement membrane, inhibiting the occurrence and progression of proteinuria. To verify the correlation between renal protection and antioxidant properties of fucoidan and its depolymerized fragments, lipid peroxidation was further detected in rat kidneys.
Malondialdehyde (MDA) and superoxide dismutase (SOD) levels in kidney tissue were measured in all groups, and MDA production was increased in the kidney tissue of the model rats, Adriamycin. Meanwhile, SOD levels in the kidney tissue of rats were decreased by Adriamycin administration. Administration of Adriamycin-induced rats with LMWF significantly increased SOD levels and decreased MDA levels in kidney tissue in a dose-dependent manner. Fucoidan administration also increased SOD levels and decreased MDA levels.
They demonstrated that both fucoidan and its depolymerized fragments successfully inhibited lipid peroxidation in the kidneys of Adriamycin-induced rats, as observed by a decrease in MDA production and an increase in SOD levels. The renal protective effect of fucoidan was due, at least in part, to its antioxidant activity.
The above experiments revealed that fucoidan and low molecular weight fucoidan also had protective effects against Adriamycin-induced nephrotic syndrome, and LMWF at the same dose showed better protective effects than fucoidan. The protective effects against nephrotic syndrome were partly related to antioxidant activity. The results suggested that both fucoidan and its depolymerized fragments showed good protective effects against Adriamycin-induced nephrotic syndrome and may be potential for the treatment of nephrotic syndrome.
Source: Mar Drugs. 2020 Feb 27;18(3):137. doi: 10.3390/md18030137