Calycosin modulates NLRP3 and TXNIP-mediated pyroptotic signaling and attenuates diabetic nephropathy progression in diabetic rats; An insight

Abstract

Diabetic nephropathy [DN] is one of the most prevalent microvascular complications of diabetes mellitus [DM] and it is considered a leading cause of kidney failure. In this study calycosin, an isoflavone that constitutes the major constituent in Radix Astragali with numerous pharmacological merits was investigated as reno-protective agent against DN and also the potential underlying mechanisms were investigated. Streptozotocin (STZ) (40 mg/kg) was injected in the peritoneal cavity of male Sprague-Dawely rats to induce DM. For ten weeks, calycosin (5 and 10 mg/kg), and NAC (500 mg/kg) were orally administered and they significantly lowered blood glucose levels, but significantly increased insulin levels. Calycosin improved the deteriorated kidney functions as evidenced in retracted serum creatinine, albuminuria, blood urea nitrogen, and proteinuria levels. Meanwhile, urine creatinine clearance significantly escalated. Furthermore, biomarkers of cell injury; LDH activity, significantly declined and kidney content of NO markedly decreased as well. Inflammation, fibrosis and oxidative stress were manifested by increased serum levels of IL-1β, renal NF-κBp65, NLRP3, TXNIP and MDA contents with declined levels of IL-10 and TAC and decreased Nrf2 expression. The above-mentioned biomarkers were significantly improved with calycosin treatment which modulated NF-κB/p65/NLRP3/TXNIP signaling, oxidative stress, inflammatory cytokines and fibrotic processes; Thus, implying a reno-protective impact. This was associated with improvement in renal histopathological and immune-histopathological parameters; H&E, Masson Trichrome and Nrf-2. Based on these findings, calycosin can be presumed to be a promising drug for hindering the development of DN through modulation of NF-κB/p65/NLRP3/TXNIP inflammasome signaling pathway.

Keywords: Calycosin; Diabetic nephropathy; NF-κB/p65; NLRP3; NrF-2; TXNIP.