Abstract 12989: Attenuation of Renal Fibrosis and Inflammation in Npr1 Haplotype Mice by Retinoic Acid and Sodium Butyrate via Interactive Modulation of STAT1, HDACs and NF-κB
Introduction: Mice lacking functional guanylyl cyclase/natriuretic peptide receptor-A (GC-A/NPRA) gene (Npr1) exhibit hypertension, kidney disease, and heart failure. In this study, we investigated the effect of butyric acid, a histone deacetylase (HDAC) inhibitor and all-trans retinoic acid (ATRA) hybrid drug (ATRA-BA) on the attenuation of renal inflammation and fibrosis in Npr1 haplotype mice.
Methods and results: Adult (18-20 week old) male Npr1 haplotype (1-copy; Npr1+/-; n=10), wild-type (2-copy; Npr1+/+; n=10), and gene-duplicated (3-copy; Npr1++/+; n=10) mice were treated with ATRA-BA (1.0 mg/kg/day) by intraperitoneal injections for 2-weeks. A significant decrease in systolic blood pressure was observed in ATRA-BA-treated Npr1+/- mice (treated, 113.3 ± 1.5 vs. control, 130.4 ± 1.9; p < 0.01; n=10). Treatments with ATRA-BA showed a marked reduction in tubulo-interstitial fibrosis (50%, p < 0.001) and a decrease in renal col 1α levels (treated, 25.9 ± 1.2 vs. control, 57.2 ± 2.9, p < 0.001) in Npr1+/- mice. Significant reduction was observed in renal IL-6 (55%, p < 0.001) and MCP-1 (61%, p < 0.01) protein levels in ATRA-BA-treated Npr1+/- mice compared with untreated controls. There was significantly increased renal NF-κB (p65) protein expression and activity in Npr1+/- mice; however, reduced levels were observed in Npr1+/++ mice compared with wild-type mice. Renal NF-κB (p65) activity decreased (52%, p < 0.01) in drug-treated Npr1+/- mice compared with controls. Treatment with ATRA-BA facilitated dissociation of HDAC1/2 from STAT1 protein complex and enhanced STAT1 acetylation. Furthermore, acetylated STAT1 formed complex with NF-κB (p65), thereby inhibiting its activity. Higher urinary albumin creatinine ratio and urinary protein was detected in Npr1+/- mice compared with Npr1+/+ mice and a complete reversal was observed in drug-treated Npr1+/- animals.
Conclusions: The present results demonstrate that ATRA-BA reduces blood pressure and repairs the abnormal renal pathology in haplotype Npr1+/- mice by modulating STAT1, HDAC1/2, NF-κB (p65) interactions. The findings will be important in developing the strategies for treating the hypertension and renal pathological conditions.
Author Disclosures: P. Kumar: None. R. Periyasamy: None. V.R. Gogulamudi: None. K.N. Pandey: None.
- © 2016 by American Heart Association, Inc.