The intricate role of annexin A2 in kidney: a comprehensive review.

Annexin A2 (Anxa2) is a calcium (Ca2+)-regulated phospholipid binding protein composed of a variable N-terminus and a conserved core domain. This protein has been widely found in many tissues and fluids, including tubule cells, glomerular epithelial cells, renal vessels, and urine. In acute kidney injury, the expression level of this protein is markedly elevated in response to acute stress. Moreover, Anxa2 is a novel biomarker and potential therapeutic target with prognostic value in chronic kidney disease. In addition, Anxa2 is associated not only with clear-cell renal cell carcinoma differentiation but also the formation of calcium-related nephrolithiasis. In this review, we discuss the characteristics and functions of Anxa2 and focus on recent reports on the role of Anxa2 in the kidney, which may be useful for future research.

Vitexin attenuates chronic kidney disease by inhibiting renal tubular epithelial cell ferroptosis via NRF2 activation.

BACKGROUND: Chronic kidney disease (CKD) involves a variety of pathological processes, and ferroptosis plays a vital role in CKD progression. Targeting ferroptosis is a promising strategy for the treatment of CKD. However, inhibitors of ferroptosis have not been used in the clinical treatment of CKD. Vitexin is a natural flavonoid with many biological activities and protective effects against various diseases. However, whether vitexin can prevent the progression of CKD is not known. METHODS: In vivo, the effect of vitexin on CKD was evaluated by using mouse models of unilateral ureteral obstruction (UUO) and unilateral ischemia-reperfusion (UIR). Western blotting, Sirius red staining and transmission electron microscopy were used to analyze renal tubular injury, interstitial fibrosis, and inflammation in the kidneys of UUO and UIR mice. In vitro, CCK8 assays and lipid peroxidation assays were performed to analyze cell viability and lipid peroxidation in human renal tubular epithelial cells (HK2 cells) induced by erastin. The activation of renal fibroblasts (NRK-49 F cells) was also analyzed. Additionally, an in-silico protein-drug docking model and coimmunoprecipitation were performed to determine the direct substrate of vitexin. RESULTS: In vivo, vitexin treatment significantly ameliorated renal tubular injury, interstitial fibrosis, and inflammation in the kidneys of UUO and UIR mice. Additionally, our results showed that vitexin significantly attenuated UUO- and UIR-induced ferroptosis in renal tubular epithelial cells by upregulating glutathione peroxidase 4 (GPX4) protein levels and inhibiting lipid peroxidation in mouse kidneys. In vitro, treatment with vitexin inhibited erastin-induced ferroptosis in HK2 cells. Moreover, vitexin inhibited the expression of collagen I and α-SMA (alpha-smooth muscle actin) in NRK-49 F cells induced by the supernatant of erastin-treated HK2 cells. Mechanistically, our results suggested that vitexin could activate the NRF2/heme oxygenase-1 (HO-1) pathway by inhibiting the KEAP1- and ubiquitination-mediated degradation of NRF2, thereby increasing the expression of GPX4, and further inhibiting lipid peroxidation and ferroptosis. Additionally, knockout of NRF2 greatly inhibited the antiferroptotic effects of vitexin. CONCLUSIONS: Taken together, our results indicate that vitexin can protect against renal tubular epithelial cell ferroptosis in CKD by activating the KEAP1/NRF2/HO-1 pathway and is a promising drug to treat CKD.

Dendrobium mixture improves gestational diabetes mellitus through regulating Nrf2/HO1 signaling pathway.

BACKGROUND: Gestational diabetes mellitus (GDM) is characterized by insulin resistance during pregnancy, and it is always combined with serious complications. Dendrobium mixture (DMix) is a kind of traditional Chinese medicine, and it has been proved to be an effective treatment for diabetes. However, the regulatory role of DMix in GDM remains elusive. METHODS: High fat feed combined with streptozotocin injection and high glucose medium were used to establish GDM animal and cell models, respectively. The levels of blood glucose, blood lipid, and insulin were measured with commercial kits. Western blotting was used to detect protein expression. RESULTS: DMix improved pancreas and placenta injury in GDM rats. DMix reversed the influence of GDM on the levels of SOD, MDA, and glutathione in the serum. Hyperglycemia and hyperlipidemia in GDM rats were suppressed by DMix. The activation of MAPK and inhibition of Nrf2/HO1 in GDM animal and cell models were reversed by DMix. The increase of ROS intensity, apoptosis, and inflammation factors in HG treated cells were reversed by DMix. CONCLUSION: This research proved that DMix improved GDM through inhibiting oxidative condition, inflammation factors, hyperglycemia and hyperlipidemia. This study might provide a novel thought for the prevention and treatment of GDM.