Berberine Reduces Renal Cell Pyroptosis in Golden Hamsters with Diabetic Nephropathy through the Nrf2-NLRP3-Caspase-1-GSDMD Pathway

Abstract

Objective. To observe the effect of berberine (BBR) on kidney cell pyroptosis in golden hamsters with diabetic nephropathy (DN) and to explore the molecular mechanism of its renal protection. Methods. Fifty clean-grade male golden hamsters were randomly divided into a control group (10) and a model building group (40). The DN model was established by high-sugar and high-fat feeding and injection of a small amount of STZ. After successful establishment of the model, they were randomly divided into a model group, western medicine group, and berberine high- and low-dose groups. The western medicine group was given irbesartan 13.5 mg/kg, and the berberine high- and low-dose groups were given BBR 200 mg/kg and 100 mg/kg, respectively, for 8 consecutive weeks. An automatic biochemical analyser was used to measure blood glucose, blood lipids, kidney function, MDA, and other indicators; radioimmunoassay was used to assess serum insulin; enzyme-linked immunosorbent assay (ELISA) was used to quantify IL-1β, IL-6, IL-18, TNF-α; HE, PAS, and Masson staining were used to observe kidney pathological tissue morphology; western blot and real-time fluorescent quantitative PCR were used to assess protein and mRNA expression of molecules, such as Nrf2, NLRP3, Caspase-1, and GSDMD; and TUNEL staining was used to detect DNA damage. SPSS statistical software was used for the data analysis. Results. The kidney tissues of golden hamsters in the control group were normal; Nrf2 was highly expressed, serum MDA level was low, NLRP3 expression in kidney tissue was not obvious, Caspase-1 and GSDMD were weakly expressed, and only a few TUNEL-positive cells were observed. Compared with the control group, the golden hamsters in the model group had obvious renal pathological damage; blood glucose, blood lipids, renal function-related indexes, insulin, and inflammatory factors IL-1β, IL-6, IL-18, and TNF-α were increased ( P < 0.05 ); NLRP3, Caspase-1, and GSDMD expression was increased; Nrf2 expression was decreased; MDA level was increased ( P < 0.05 ); and the number of TUNEL-positive cells was increased. Compared with the model group, the pathological morphology of the kidney tissue of golden hamsters in the three treatment groups was significantly improved; blood glucose, blood lipids, renal function, and the expression of inflammatory factors IL-1β and IL-6 were reduced ( P < 0.05 ); NLRP3, Caspase-1, GSDMD, and other molecular proteins and mRNA expression were decreased; Nrf2 expression was increased; MDA level was decreased ( P < 0.05 ); and the number of TUNEL-positive cells was decreased. Conclusion. DN golden hamster kidney NLRP3-Caspase-1-GSDMD signalling was enhanced. BBR can reduce oxidative stress damage by regulating antioxidative Nrf2 and then regulating NLRP3-Caspase-1-GSDMD signalling to inhibit pyroptosis, antagonizing DN inflammation-induced damage.

The protection afforded by Berberine against chemotherapy‐mediated nephropathy in rats involves regulation of the antioxidant axis

“…This is not strange with this compound as daily administration of BBR attenuated not only renal damage in DOX-treated animals but also in other renal conditions induced by other injurious stimuli, including ischaemia, ischaemia/reperfusion, hyperglycaemia, streptozotocin, hypertension, high glucose, and toxins (i.e., diclofenac), and was mediated mainly by suppressing oxidative damage, inhibiting inflammation, and increasing levels of the endogenous glutathione (GSH) and antioxidant enzymes. 31,35,[38][39][40][41]53 DOX-induced, high quantities of ROS are crucial for the induction of renal damage and proteinuria by promoting renal inflammation, fibrosis, and apoptosis. 12,13,54 In this context, DOX generates ROS within the cells by upregulating scavenging antioxidants, activating ROSgenerating enzymes, promoting mitochondria damage, and forming Fe+2-DOX adducts.…”

“…In this view, BBR prevented DM-induced renal cell pyroptosis by decreasing the expression of NRLP3 inflammasome and caspase-3, as well as lowering levels of numerous inflammatory mediators in antioxidant-related mechanisms that involved stimulating MnSOD. 41 In the same line, BBR ameliorated gentamycin-induced nephrotoxicity and apoptosis in rats by increasing GSH and SOD levels, as well as stimulating Bcl2. 57 Also, BBR attenuated diclofenac-mediated renal damage in rats by stimulating SOD and glutathione reductase (GHSR).…”

“…[33][34][35][36] Having the kidney in particular, the nephroprotective effects of BBR was also shown in vitro and in vivo in numerous renal injury animal models. 31,35,[37][38][39][40][41] Interestingly, the hepatic and neural protective effect of BBR against hyperglycaemia and diabetes mellitus (DM)-mediated renal injury, as well as in other models such as fed high-fat diet (HFD) and carbon tetrachloride (CCl4) models. [32][33][34]39,41,42 In the same line, BBR attenuated hepatic steatosis and damage in rats by activating Nrf2.…”

“…31,35,[37][38][39][40][41] Interestingly, the hepatic and neural protective effect of BBR against hyperglycaemia and diabetes mellitus (DM)-mediated renal injury, as well as in other models such as fed high-fat diet (HFD) and carbon tetrachloride (CCl4) models. [32][33][34]39,41,42 In the same line, BBR attenuated hepatic steatosis and damage in rats by activating Nrf2. A similar mechanism of protection was shown in the neural cells exposed to oxidants.…”

Corrigendum to “Berberine Reduces Renal Cell Pyroptosis in Golden Hamsters with Diabetic Nephropathy through the Nrf2-NLRP3-Caspase-1-GSDMD Pathway”

“…In the article titled “Berberine Reduces Renal Cell Pyroptosis in Golden Hamsters with Diabetic Nephropathy through the Nrf2-NLRP3-Caspase-1-GSDMD Pathway” [ 1 ], there are some errors to be corrected as follows: In Section 2.1, it should be stated that the animals were purchased from Hebei Yiweiwo Biological Technology Co., Ltd. (license number: SCXK (Hebei) 2018–002). In Section 2.4, the description of how the animals were grouped should be clarified as follows: “Fifty golden hamsters were randomly divided into a control group (10) and a model building group (40).…”