Role for histone deacetylases in regulating angiotensinogen expression mediated by the JAK‐STAT pathway by suppressor of cytokine signaling in renal proximal tubular cells (1173.2)

Abstract

Activated JAK‐STAT pathway stimulates SOCS expression, which inhibits JAK‐STAT pathway as a negative‐feedback system. Elevated SOCS limits AGT augmentation in PTC, suggesting that induction of SOCS elevation is an effective strategy to treat the renin‐angiotensin system (RAS) associated diseases. Thus, establishment of an approach to elevate SOCS without activation of the JAK‐STAT pathway is required. The aim of this study was to demonstrate that epigenetic modification by pharmacological treatments induces SOCS elevation leading to AGT suppression in PTC. Rat PTC were treated with sodium butyrate (NaB), a non‐selective HDAC inhibitor, for 6 hours. NaB induced SOCS1 (1.71 ± 0.04, ratio to control) and SOCS3 (1.67 ± 0.2) mRNA elevation in PTC. In the NaB‐treated cells, decreases in STAT3 phosphorylation levels (0.56 ± 0.02), AGT mRNA (0.19 ± 0.04) and protein (0.76 ± 0.04) levels were observed. PCI‐34051, an HDAC inhibitor exhibiting higher affinity to HDAC8 than other HDACs, also suppressed AGT expression. Inversely, Inhibition of class IIa HDACs by TMP269 increased AGT expression, indicating that class IIa HDACs include a repressor of AGT expression. These results suggest that an important role for HDACs, particularly HDAC8, in regulating AGT expression via the JAK‐STAT pathway in PTC. The findings will provide a more effective approach to treat RAS associated diseases by SOCS elevation.