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Abstract: TH-PO850

Active Vitamin D Regulates Macrophage M1/M2 Phenotypes via the STAT-1-TREM-1 Pathway in Diabetic Nephropathy

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

  • Zhao, Yu, Institute of Nephrology, Zhong Da Hospital, Southeast University, School of Medicine, Nanjing, China
  • Jiang, Yuteng, Institute of Nephrology, Zhong Da Hospital, Southeast University, School of Medicine, Nanjing, China
  • Zhu, Xiaodong, Institute of Nephrology, Zhong Da Hospital, Southeast University, School of Medicine, Nanjing, China
  • Zhang, Xiaoliang, Zhong Da Hospital, Southeast University, School of Medicine, Nanjing, JIANGSU , China
Background

Imbalance of M1/M2 macrophages phenotype activation is a key point in diabetic nephropathy (DN). TREM-1(Triggering Receptor Expressed On Myeloid Cells 1) is essential for macrophage function regulation. Signal transducer and activator of transcription (STAT) is a key factor that regulates the activation of macrophage M1/M2 phenotypes. Our previous studies indicated that active vitamin D (VD) has renoprotective role. This study aimed to investigate whether VD suppresses macrophage transition to the M1 phenotype via inhibiting the high glucose-induced STAT-1 phosphorylation to reduce TREM-1 expression.

Methods

Pathological changes in kidney tissue were detected and the expression of CD68 TREM-1, STAT-1, M1 makers and M2 makers were acquired in renal tissue of DN patients and 18w DN rats. In vitro, RAW 264.7 cells were treated by high glucose with or without VD. TREM-1 siRNA, STAT-1 siRNA and high expression plasmid of TREM-1 and STAT-1 were explored to elucidate the underlying mechanism. The expression of TREM-1 and STAT-1 and the changes of macrophage phenotype were examined separately by Western Blot, immunofluorescence stain.

Results

(1) In DN patients, the expression of M1 markers (iNOS, TNF-α) and TREM-1, pSTAT-1 were increased in comparation with NC group(P<0.05). Additionally, iNOS expression was positive correlated with the TREM-1 expression (r=0.757, P<0.05), pSTAT-1 (r=0.808, P<0.05 ). (2) In DN rats, the enlargement of glomerular surface area, expansion of glomerular mesangial matrix, the expression of CD68, TREM-1, pSTAT-1 and M1 markers (iNOS) were significantly increased compared with NC group (P<0.05), while above changes were markedly decreased in DN+VD group (P<0.05). (3) In vitro, VD significantly decreased high glucose induced CD68, TREM-1, pSTAT-1 and M1 markers (iNOS) expression. However, above effects from VD were abolished when TREM-1 or STAT-1 expression was overexpressed by TREM-1 or STAT-1 plasmid. Inhibition of STAT-1 expression with STAT-1 siRNA decreased TREM-1 expression, while, TREM-1 regulation by TREM-1 siRNA or TREM-1 overexpression techniques did not affect STAT-1 expression.

Conclusion

VD can inhibit macrophage transition to the M1 phenotype through the STAT-1/TREM-1 pathway under high glucose condition.