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Objective: To explore the mechanism of EPO on activating receptors of NK cells in rats with diabetic nephropathy based on HMGB1/Beclin-1 signaling pathway. Methods: Forty SPF male SD rats were randomly divided into normal group （A）， model group （B）， metformin group （C） and EPO group （D）， with 10 rats in each group. Diabetic nephropathy modeling was performed on groups B， C and D using high-fat diet and streptozotocin. After successful modeling， group C was given metformin 100 mg/kg by intra-gastric administration， and group D was intraperitoneal injection of EPO 100 U/kg. Group A and B were given normal saline at the same volume by intragastric administration simultaneously. After successful modeling， the remaining 20 rats were randomly divided into group E and group F. Group E was given 30 mg/kg HMGB1 inhibitor by intragastric administration， group F was given 30 mg/kg HMGB1 inhibitor by intragastric administration and 100 U/kg EPO by intraperitoneal injection. HK-2 cells were taken and divided into high glucose+HK-2 cells （HH） group， EPO+high glucose+HK-2 cells （EH） group， glycyrrhizin L+high glucose+HK-2 cells （LH） group， and cultured with glucose for cell experiment. Blood glucose was detected by glucose analyzer， biochemical indexes were de-tected by automatic biochemical analyzer， and renal pathological morphology of rats was detected by PAS staining. Expression of HMGB1/Beclin-1 protein was detected by Western blot， and expressions of NK cell activated receptors were detected by RT-PCR and immunohistochemistry. Results: Compared with group A， blood glucose， 24 h urine volume， blood glucose curve， BUN， Scr， UAlb contents in blood and urine， mRNA and protein expressions of NKp30， NKp44， NKp46 in group B were significantly increased （P< 0.05）， while body weight was significantly decreased （P<0.05）. Compared with group B， blood glucose， 24 h urine volume， blood glucose curve， BUN， Scr， UAlb contents in blood and urine， mRNA and protein expression of NKp30， NKp44 and NKp46 in group C and group D were significantly decreased （P<0.05）， while body weight was significantly increased （P<0.05）， renal pathology was also significantly improved， the changes of group D was significantly higher than that of group C （P<0.05）. Compared with group A， expression of HMGB1/Beclin-1 protein in renal tissues of rats in group B was significantly increased （P<0.05）， and expression of HMGB1/Beclin-1 protein in renal tissues of rats in groups C， D， E and F was significantly decreased （P<0.05）， expression of HMGB1/Beclin-1 protein in group D was significantly decreased compared with group C （P<0.05）， there was no significant difference between group E and group D， and expression of HMGB1/Beclin-1 protein in group F was significantly decreased compared with group E. HMGB1/Beclin-1 protein expression was positively correlated with NKp30， NKp44 and NKp46 mRNA （P<0.05）. Compared with HH group， proliferation rates of EH and LH groups were significantly increased （P<0.05）， while apoptosis rate and HMGB1/Beclin-1 protein expression were significantly decreased （P<0.05）， there was no significant difference between LH group and EH group （P> 0.05）. Conclusion: EPO can effectively reduce expressions of NK cell activated receptors and inhibit HMGB1/Beclin-1 signaling path-way in diabetic nephropathy rats， suggesting that EPO may exert its effect by regulating NK cell activated receptors and HMGB1/Beclin-1 signaling pathway. NK cell activation receptors expressions are positively correlated with HMGB1/Beclin-1 signaling pathway. [ABSTRACT FROM AUTHOR]

nscription factor-κB (NF-κB) signaling pathway, and its effect on renal fibrosis in diabetic nephropathy (DN) rats. Methods: A rat DN model was established, and the renal tubular epithelial cells (NRK-52E) were cultured with high sugar to simulate an in vitro DN model, qRT-PCR was used to detect the expression level of miR-203, Western blot was used to detect the expressions of PEG3 and NF-κB proteins. Dual luciferase reporter gene technology was used to detect the targeting relationship between miR-203 and PEG3. The miR-203 mimic (miR-203 mimic) and negative control (mimic NC), PEG3 high expression recombinant vector (pcDNA-PEG3) and negative control (pcDNA-NC) were constructed, and injected and transfected into DN rats and DN model cells respectively to set the control group, model group, miR-203 mimic group, mimic NC group, miR-203 mimic+pcDNA-PEG3 group, and miR-203 mimic+pcDNA-NC group. The 24 h urine protein, blood sugar, serum creatinine (SCr) and urea nitrogen (BUN) in rats were detected, electron microscopy and Masson staining were used to detect renal tissue lesions and fibrosis changes; ELISA was used to detect the contents of IL-6, IL-1β, Collagen Ⅰand TGF-β1 in cells； Western blot was used to detect the protein expressions of IL-6, IL-1β, Collagen Ⅰ，α-SMA and TGF-β1 in kidney tissue. Results: The expressions of miR-203 in kidney tissue and renal tubular epithelial cells of DN rats were decreased (P<0.05), the expression of PEG3/NF-κB was increased in kidney tissue and renal tubular epithelial cells of DN rats (P<0.05). There was a targeted binding site between miR-203 and PEG3. Up-regulating the expression of miR-203 could inhibit the activation of PEG3/NF-κB in DN rats and cell models, reduce the expression of inflammation-fibrosis related factors, and alleviate the pathological symptoms of DN such as renal tissue structural damage and decreased renal function in rats (P<0.05). pcDNA-PEG3 could partially reverse the above effects of miR-203(P<0.05). Conclusion: miR-203 can target to negatively regulate the PEG3/NF-κB pathway and up-regulate the expression of miR-203, which can target to inhibit the activation of the PEG3/NF-κB pathway and play the role of anti-inflammatory-fibrosis in the kidney of DN rats. [ABSTRACT FROM AUTHOR]