Abstract
Background/Aims: Previous studies have suggested that myricetin (Myr) could promote the expression and nuclear translocation of nuclear factor (erythroid-derived 2)-like (Nrf2). This study aimed to investigate whether Myr could attenuate diabetes-associated kidney injuries and dysfunction in wild-type (WT) and Nrf2 knockdown (Nrf2-KD) mice. Methods: Lentivirus-mediated Nrf2-KD and WT mice were used to establish type 1 diabetes mellitus (DM) by streptozotocin (STZ) injection. WT and Nrf2-KD mice were then randomly allocated into four groups: control (CON), Myr, STZ, and STZ + Myr. Myr (100 mg/kg/day) or vehicle was administered for 6 months. Kidneys were harvested and weighed at the end of the experiment. Hematoxylin and eosin staining and Masson’s trichrome staining were used to assess the morphology and fibrosis of the kidneys, respectively. Urinary albumin-to-creatinine ratio was used to test renal function. Western blotting was performed to determine oxidative-stress- or inflammation-associated signaling pathways. Real-time polymerase chain reaction (RT-PCR) was performed to detect the expression of fibrosis or inflammatory cytokines at the message Ribonucleic Acid (mRNA) level. Results: In WT mice, Myr alleviated DM-induced renal dysfunction, fibrosis, and oxidative damage and enhanced the expression of Nrf2 and its downstream genes. After knockdown of Nrf2, Myr treatment partially but significantly mitigated DM-induced renal dysfunction and fibrosis, which might be associated with inhibition of the I-kappa-B (IκB)/nuclear factor-κB (NF-κB) (P65) signaling pathway. Conclusions: This study showed that Myr prevented DM-associated decreased expression of Nrf2 and inhibited IκB/NF-κB (P65) signaling pathway. Moreover, inhibition of IκB/NF-κB (P65) signaling pathway is independent of the regulation of Nrf2. Thus, Myr could be a potential treatment for preventing the development and progression of DM-associated kidney injuries and dysfunction.
Highlights
Diabetic nephropathy (DN) is one of the major complications of diabetes mellitus (DM)
The results revealed that STZ injections caused a much higher Urinary albumin-to-creatinine ratio (UACR) compared with the Con group, and Myr treatment prevented this change (Figure 1G)
We analyzed kidney fibrosis after Nrf2 knockdown, and the results showed that STZ-induced DM caused visible fibrosis, increased glycogen deposition, transforming growth factor (TGF)-β/ Smad pathway activation, and the secretion of collagen I and collagen III, all of which were alleviated by Myr treatment after Nrf2 knockdown (Figure 6A–H)
Summary
Diabetic nephropathy (DN) is one of the major complications of diabetes mellitus (DM). 30–40% of patients with diabetes develop DN, and one-third of them progress to endstage renal disease (ESRD) (Tesch, 2017). There is currently no effective therapy available for ESRD patients except for dialysis and transplantation. Patients undergoing dialysis still have a high mortality rate of 20% per year (DeFronzo et al, 2017), and the shortage of donor kidneys largely restricts the number of transplantations (DeFronzo et al, 2017). Strategies for DN treatment mainly focus on glycemic and blood pressure control, and there is no effective therapy for blocking the progression of renal failure initiated through DN (Lacava et al, 2017). Because of the high morbidity of DN and the rapidly increasing numbers of diabetic patients worldwide, new effective treatments are urgently needed to counter DM-associated kidney injuries and dysfunction
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