Promotion of chemerin in rat diabetic kidney disease through enhancement of TGF-β1/Smads/CTGF pathway.
2021
OBJECTIVE Although increasing evidence shows that the adipokine chemerin is involved in diabetic kidney disease (DKD), it is still unclear whether the chemerin acts as a critical element in renal function through the signaling pathways of transforming growth factor β1/Smads/connective tissue growth factor (TGF-β1/Smads/CTGF) in the context of DKD. Therefore, we sought to determine the role of chemerin and TGF-β1/Smads/CTGF signaling pathway in the development and/or progression of DKD. METHODS We used rat renal mesangial cells (RMCs) and a DKD rat model as study subjects. RMCs and rats were randomly separated into different groups and transfected with the constructed chemerin expression vector pcDNA™ 3.1 (+)-chemerin. Rat renal function and inflammatory cytokines were assessed after treatment with chemerin or CCX832 (ChemR23 antagonist). Real time polymerase chain reverse transcription (RT-QPCR) was used to detect the mRNA expressions of TGF-β1, Smad2, Smad4, and CTGF. Western blot was performed to determine protein expression for semiquantitative analysis. RESULTS In in vitro studies, the mRNA and protein levels of TGF-β1, Smad2, Smad4, and CTGF were significantly increased in the groups of high glucose and chemerin as compared to the normal control and normal glucose groups, most notably in the high glucose chemerin group (all P<0.05). In vivo studies revealed that the mRNA and protein levels of TGF-β1, Smad2, Smad4, and CTGF were higher in the DKD group and the normal chemerin group than in the normal control group and the blocking receptor group, while appearing the highest in the DKD chemerin group (all P<0.05). Moreover, kidney/body weight ratio, urea, creatinine, and urine protein were increased, and the weight and endogenous creatinine clearance rate decreased in the DKD group and the normal chemerin group (all P<0.05). These changes were more pronounced in the DKD chemerin group. At the same time, blood glucose, triglycerides (TGs), and total cholesterol (TC) in the blocked receptor group was lower than those in the DKD group and the DKD chemerin group (all P<0.05). In contrast to those in the normal control group and blocked receptor group, tumor necrosis factor alpha (TNF-α) and interleukin (IL)-1 showed higher concentrations in the DKD group and the normal chemerin group. This result was more pronounced in the DKD chemerin group (all P<0.05). CONCLUSION Chemerin may play a role in DKD by enhancing the signaling pathways of TGF-β1/Smads/CTGF transduction either in vitro or in vivo. Moreover, high glucose accelerates kidney injury by activating fibrotic pathways.
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