Biochanin A Ameliorates Nephropathy in High-Fat Diet/Streptozotocin-Induced Diabetic Rats: Effects on NF-kB/NLRP3 Axis, Pyroptosis, and Fibrosis

Abstract

Nephropathy is the most prevalent microvascular disorder in diabetes mellitus. Oxidative stress and inflammatory cascade provoked by the persistent hyperglycemic milieu play integral roles in the aggravation of renal injury and fibrosis. We explored the impact of biochanin A (BCA), an isoflavonoid, on the inflammatory response, nod-like receptor protein 3 (NLRP3) inflammasome activation, oxidative stress, and fibrosis in diabetic kidneys. A high-fat-diet/streptozotocin (HFD/STZ)-induced experimental model of diabetic nephropathy (DN) was established in Sprague Dawley rats, and in vitro studies were performed in high-glucose-induced renal tubular epithelial (NRK-52E) cells. Persistent hyperglycemia in diabetic rats was manifested by perturbation of renal function, marked histological alterations, and oxidative and inflammatory renal damage. Therapeutic intervention of BCA mitigated histological changes, improved renal function and antioxidant capacity, and suppressed phosphorylation of nuclear factor-kappa B (NF-κB) and nuclear factor-kappa B inhibitor alpha (IκBα) proteins. Our in vitro data reveal excessive superoxide generation, apoptosis, and altered mitochondrial membrane potential in NRK-52E cells that were cultured in a high-glucose (HG) environment were subsided by BCA intervention. Meanwhile, the upregulated expressions of NLRP3 and its associated proteins, the pyroptosis-indicative protein gasdermin-D (GSDMD) in the kidneys, and HG-stimulated NRK-52E cells were significantly ameliorated by BCA treatment. Additionally, BCA blunted transforming growth factor (TGF)-β/Smad signaling and production of collagen I, collagen III, fibronectin, and alfa-smooth muscle actin (α-SMA) in diabetic kidneys. Our results indicate the plausible role of BCA in attenuating DN, presumably through modulation of the apoptotic cascade in renal tubular epithelial cells and the NF-κB/NLRP3 axis.

Age characteristics of myocardial blood supply in comorbid pathology

“…The end products of glycosylation can also activate endothelial cells, which leads to the expression of prothrombotic factors and the initiation of a cascade of coagulation mechanisms and formation of microthrombi [20], which we found in myocardial micro-hemo-vessels on the 56 th day of the experiment. In addition, the end products of glycosylation interact with their cellular receptors, such as RAGE, to promote the production of active oxygen species (AOS) and activation of the nuclear factor-κB (NF-κB) signalling pathway, which lead to endothelial cell death through pyroptosis [21]. Glycosylation end products trigger a chain reaction of activation of pro-inflammatory cytokines, chemokines and adhesion molecules, promoting the migration of inflammatory cells and the continuation of inflammation in the vascular wall [22].…”

Nephroprotective Effect of Bergapten Against Cyclophosphamide-Mediated Renal Stress, Inflammation, and Fibrosis in Wistar Rats: Probable Role of NF-kB and TGF-β1 Signaling Molecules

“…TGF-β1 becomes active when exposed to oxidative stress or inflammatory cytokines and binds to the respective receptors . Activated TGF-β1 modulates the NF-kB pathway and potentiates mesangial cells’ collagen production and proliferation, leading to the deposition of matrix and renal fibrosis. , Considering these facts, we also studied the effect of CPM on renal fibrosis. We found that CPM exposure significantly increased the collagen deposition area, as evidenced by MT staining.…”

Harnessing the Power of Polyphenols: A New Frontier in Disease Prevention and Therapy

“…The inhibition of PAR-2 has been found to enhance autophagy while preventing inflammation and fibrosis [86]. Contrary to expectations, biochanin A mitigates diabetic nephropathy by downregulating the expression of the TGF-β1 and PAR-2 genes [65,81,82].…”

“…The inhibition of PAR-2 has been found to enhance autophagy while preventing inflammation and fibrosis [86]. Contrary to expectations, biochanin A mitigates diabetic nephropathy by downregulating the expression of the TGF-β1 and PAR-2 genes [65,81,82]. Among the numerous health benefits of isoflavones, biochanin A is widely recognized for its anti-inflammatory, antihyperlipidemic, antioxidant, and anticancer attributes by suppressing TGF-β1 and PAR-2 gene expression in kidney tissues of STZ-induced diabetic rats [80][81][82].…”

“…Investigations conducted in laboratory settings as well as on living organisms have shown that myricitrin can mitigate oxidative stress by stimulating nuclear factor erythroid 2-related factor 2 (Nrf-2) and counteracting oxidative radicals effectively (Figure 4) [72,79]. Among the numerous health benefits of isoflavones, biochanin A is widely recognized for its anti-inflammatory, antihyperlipidemic, antioxidant, and anticancer attributes by suppressing TGF-β1 and PAR-2 gene expression in kidney tissues of STZ-induced diabetic rats [80][81][82]. In addition to its antioxidant properties, biochanin A appears to exert an anti-diabetic influence.…”