<p>The Effects of Puerarin on Autophagy Through Regulating of the PERK/eIF2α/ATF4 Signaling Pathway Influences Renal Function in Diabetic Nephropathy</p>

Abstract

Background and Purpose: Autophagy is the main protective mechanism against aging in podocytes, which are terminally differentiated cells that have a very limited capacity for mitosis and self-renewal. Here, a streptozotocin-induced DN C57BL/6 mouse model was used to investigate the effects of puerarin on the modulation of autophagy under conditions associated with endoplasmic reticulum stress (ERS). In addition, this study aimed to identify the potential underlying molecular mechanisms. Methods and Results: DN C57BL/6 mouse model was induced by streptozotocin (150 mg/ kg) injection. The mice were administered rapamycin and puerarin, respectively, daily for up to 8 weeks. After the serum and kidney samples were collected, the fasting blood glucose (FBG), parameters of renal function, histomorphology, and the podocyte functional proteins were analyzed. Moreover, the autophagy markers and the expressions of PERK/ATF4 pathway were studied in kidney. Results found that the FBG level in DN mice was significantly higher than in normal mice. Compared with DN model mice, puerarin-treated mice showed an increased expression of podocyte functional proteins, including nephrin, podocin, and podocalyxin. Furthermore, the pathology and structure alterations were improved by treatment with rapamycin and puerarin compared with the DN control. The results indicated an elevated level of autophagy in rapamycin and puerarin groups compared with the DN model, as demonstrated by the upregulated expression of autophagy markers Beclin-1, LC3II, and Atg5, and downregulated p62 expression. In addition, the levels of PERK, eIF2α, and ATF4 were reduced in the DN model, which was partially, but significantly, prevented by rapamycin and puerarin. Conclusion: This study emphasizes the renal-protective effects of puerarin in DN mice, particularly in the modulation of autophagy under ERS conditions, which may be associated with activation of the PERK/eIF2α/ATF4 signaling pathway. Therefore, PERK may be a potential target for DN treatment.

Effects of puerarin on chronic inflammation: Focus on the heart, brain, and arteries

“… 26 , 27 Puerarin significantly reduced the expression of the receptor for advanced glycation end products (RAGE), improved autophagy function via upregulation of its essential components of beclin, microtubule‐associated protein 1A/1B‐light‐chain 3 (LC3II), and autophagy related 5 (ATG5), increased the antioxidant activity of heme oxygenase (HO) and the anti‐aging molecule SIRT1 expression, alleviated endoplasmic reticulum (ER) stress, reduced hyperglycemia, and eventually improved renal function in diabetic rats. 28 , 29 , 30 In addition, puerarin lowered insulin resistance, and nuclear factor kappa B (NF‐κB) mediated inflammation, and prevented the incidence of gestational diabetes in rats fed a high fat diet. 31 Taken together, the above studies indicate that puerarin has potential as a functional food therapeutic for the obesity, metabolic syndrome, diabetes mellitus, and their complications.…”

“…Puerarin diminished hyperglycemia and exerted a cardiac protective role by reducing cardiomyocyte hypertrophy and cardiac fibrosis in diabetic rats induced by STZ 26,27 . Puerarin significantly reduced the expression of the receptor for advanced glycation end products (RAGE), improved autophagy function via upregulation of its essential components of beclin, microtubule‐associated protein 1A/1B‐light‐chain 3 (LC3II), and autophagy related 5 (ATG5), increased the antioxidant activity of heme oxygenase (HO) and the anti‐aging molecule SIRT1 expression, alleviated endoplasmic reticulum (ER) stress, reduced hyperglycemia, and eventually improved renal function in diabetic rats 28–30 . In addition, puerarin lowered insulin resistance, and nuclear factor kappa B (NF‐κB) mediated inflammation, and prevented the incidence of gestational diabetes in rats fed a high fat diet 31 .…”

Deciphering the Pharmacological Mechanisms of Qidan Dihuang Decoction in Ameliorating Renal Fibrosis in Diabetic Nephropathy through Experimental Validation In Vitro and In Vivo

“…Berberrubine, a primary metabolite of berberine [31], was demonstrated to have the effect of suppressing the expression of gluconeogenic genes, reducing hepatic gluconeogenesis, and lowering blood glucose [32]. Przewaquinone A is one of the hydroxylated metabolites of tanshinone IIA [33], which has been proven to ameliorate the thickening of the glomerular basement membrane and the collagen deposition in the renal tissues of streptozotocin-induced diabetic rats via attenuating PERK/ p-elf2α/ATF-4 signaling activities [34]. We confirmed the efficacy of QDD in preventing renal fibrosis in type 2 diabetic db/db mice.…”

Molecular Mechanism of Puerarin Against Diabetes and its Complications

“…In addition, Puerarin could restrain the protein expressions of TGF-β1 and TGF-β1 receptors (TGF-β-RI) in the kidney tissue of KKAy mice via reducing the expression of α-smooth muscle actin (α-SMA) ( Yi et al, 2013 ). It also inhibited the TLR4/MyD88/NF-kBp65 pathway by up-regulating miRNA-140-5p, thus reducing expression levels of TNF-α, interleukin-1β (IL-1β), interleukin-6 (IL-6), interferon-γ (INF-γ), and TGF-β1 in renal tissues of diabetic rats ( Xu X et al, 2020 ). These changes may inhibit and reverse the epithelial-mesenchymal transition process, thus delaying the occurrence, preventing diabetes-induced renal damage and the development of DN.…”