Kidney Week

Abstract: SA-PO1000

Critical Role of Histone Deacetylase 3 in the Pathogenesis of Hypertensive Kidney Disease

Session Information

• Hypertension and CVD: Mechanisms - II
  October 27, 2018 | Location: Exhibit Hall, San Diego Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Hypertension and CVD

• 1403 Hypertension and CVD: Mechanisms

Authors

• An, Changlong, Baylor College of Medicine, Houston, Texas, United States

Changlong An,

• Wen, Jia, Baylor College of Medicine, Houston, Texas, United States

Jia Wen,

• Thomas, Sandhya S., Baylor College of Medicine, Houston, Texas, United States

Sandhya S. Thomas,

• Hu, Zhaoyong, Baylor College of Medicine, Houston, Texas, United States

Zhaoyong Hu,

• Mitch, William E., Baylor College of Medicine, Houston, Texas, United States

William E. Mitch,

• Wang, Yanlin, Baylor College of Medicine, Houston, Texas, United States

Yanlin Wang,

Background

Hypertension is a major cause of chronic kidney disease, which is characterized byinflammation and fibrosis. However, the underlying molecular mechanisms are not fully understood. In this study, we examined the function role of histone deacetylase 3 (HDAC3) in renal inflammation and fibrosis in a mouse model of angiotensin II-induced hypertension.

Methods

Myeloid HDAC3 knockout mice were generated by crossing HDAC3^f/fmice with Lyz-Cre mice. Both Lyz-Cre^-/-HDAC3^f/fmice and Lyz-Cre^+/+HDAC3^f/fmice were infused with angiotensin II at 1.5ug/kg/min or vehicle for 28 days. Blood pressure was monitored by tail-cuff method. Renal function was assessed by measuring blood urea nitrogen (BUN). Kidney sections were prepared and stained for histological and immunological analysis. Western blot analysis was performed to detect the levels of fibronectin and a-SMA. Quantitative RT-PCR was performed to examine mRNA levels of proinflammatory cytokines. Cultured macrophages were used to study the role of HDAC3 in proinflammatory molecule expression in vitro.

Results

There is no significant difference in blood pressure at baseline. Blood pressure increased after angiotensin II treatment in both Lyz-Cre^-/-HDAC3^f/f and Lyz-Cre^+/+HDAC3^f/f mice that are similar between the two treatment groups. Compared with Lyz-Cre^-/-HDAC3^f/f mice, mice with myeloid HDAC3 deficiency were protected from angiotensin II-induced renal injury with lower BUN. Furthermore, mice with HDAC3 deficiency in myeloid cells accumulated significantly fewer macrophages, T cells, and myeloid fibroblasts. HDAC3 deficiency in myeloid cells significantly reduced the mRNA expression of pro-inflammatory molecules the kidney after angiotensin II treatment. HDAC3 deficiency in myeloid cells significantly attenuated the protein levels of fibronectin and a-SMA and markedly inhibited collagen deposition in the kidney following angiotensin II treatment. In cultured macrophages, knockdown of HDAC3 with shRNA suppressed pro-inflammatory molecule expression. Furthermore, knockdown of HDAC3 inhibited NF-kB p65 binding to IL-6 promoter.

Conclusion

Our study identifies a critical role of HDAC3 in the regulation of hypertension-induced renal inflammation and fibrosis. Therefore, targeting HDAC3 may represent a novel therapeutic strategy for hypertensive kidney disease.

Funding

• NIDDK Support