Viscum coloratum polysaccharide ameliorates hyperuricemic nephropathy by upregulating Nrf2 to inhibit TGF-β1/Smad3 and NLRP3/ASC/Caspase-1 pathways.

ETHNOPHARMACOLOGICAL RELEVANCE: Viscum coloratum (Kom.) Nakai is a commonly used traditional Chinese medicine (TCM) in the treatment of diseases such as tumors, diabetes, gout, and hepatitis. Viscum coloratum polysaccharide (VCP) is a major component of this TCM. however, its mechanism of action in hyperuricemic nephropathy (HN) remains unclear.

AIM OF THE STUDY: This study aimed to elucidate the mechanisms and pathways by which VCP exerts its effects in HN rats.

MATERIALS AND

METHODS

The functional groups, molecular weight, monosaccharide compositions, and micromorphologies of VCP were characterized using FT-IR, HPGPC, HPAEC, and SEM, respectively. A rat model of HN was established using a combination of potassium oxonate and adenine. The potential mechanism of action of VCP in alleviating HN was verified using Elisa kit, histopathological examination, Western blot, and immunofluorescence. Additionally, 16S rRNA gene sequencing was employed to detect the regulatory effect of VCP on the gut microbiota in HN rats. An in vitro model of HN was also constructed by stimulating HK-2 cells with uric acid. Finally, the underlying mechanism was further validated using small interfering RNA to silence the expression of Nrf2 in HK-2 cells.

RESULTS

VCP is a neutral homogeneous polysaccharide with a molecular weight of 8.91 × 104 Da and is composed of Glc and Man. VCP enhanced the ability of the kidney to metabolize UA by inhibiting the expression of URAT1 and increasing that of ABCG2. It also increased species richness and diversity, enriched the abundance of Lactobacillus, Peptostreptococcaceae, and Ruminococcus, regulated gut microbiota imbalance, improved the intestinal capacity to metabolize uric acid, and reduced UA levels in HN rats. VCP activated the Nrf2/HO-1 pathway by upregulating Nrf2 expression, increased the activity of kidney antioxidant, attenuated kidney oxidative damage, and inhibited the downstream NLRP3/ASC/Caspase-1 and TGF-β1/Smad3 pathways to alleviate the symptoms of kidney tubular inflammation and fibrosis, while exerting a protective effect against kidney injury in HN rats.

CONCLUSIONS

VCP decreased uric acid levels in HN rats by regulating the pathways related to urate transporters and gut microbiota. It also upregulated Nrf2 expression to inhibit the NLRP3/ASC/Caspase-1 and TGF-β1/Smad3 signaling pathways, and protecting against HN kidney injury.