Abstract: SA-PO1081

Mocetinostat Attenuates Renal Injury and Dysfunction via the Inhibition of HDAC in Npr1 Gene-Targeted Mutant Mouse Models

Session Information

Category: Hypertension

  • 1102 Hypertension: Basic and Experimental - Renal Causes and Consequences

Authors

  • Kumar, Prerna, Tulane University Health Sciences Center and School of Medicine, New Orleans, Louisiana, United States
  • Nguyen, Christian, Tulane University Health Sciences Center and School of Medicine, New Orleans, Louisiana, United States
  • Gogulamudi, Venkateswara R, Tulane University Health Sciences Center and School of Medicine, New Orleans, Louisiana, United States
  • Samivel, Ramachandran, Tulane University Health Sciences Center and School of Medicine, New Orleans, Louisiana, United States
  • Pandey, Kailash Nath, Tulane University Health Sciences Center and School of Medicine, New Orleans, Louisiana, United States
Background

Mice lacking functional guanylyl cyclase/natriuretic peptide receptor-A (GC-A/NPRA) gene (Npr1) exhibit hypertension and heart failure. The objective of the present study was to elucidate the effect of class I histone deacetylase (HDAC) inhibitor, mocetinostat (MGCD) on the regulation of Npr1 expression and repair of renal injury and dysfunction in Npr1 heterozygous mutant mice.

Methods

Male Npr1 gene-disrupted heterozygous (1-copy; Npr1+/-), wild-type (2-copy; Npr1+/+) and gene-duplicated (3-copy; Npr1++/+) mice were injected intraperitonealy with MGCD (2 mg/kg) at alternate days for 2-weeks.

Results

The treatment with MGCD significantly increased renal NPRA protein and cGMP levels in all three mice genotypes (Npr1+/-, Npr1+/+, and Npr1++/+) compared with vehicle-treated controls. The Npr1+/- mice exhibited significantly increased renal HDAC activity and HDAC1/2 protein levels compared with Npr1+/+ and Npr1++/+ mice. MGCD treatment attenuated HDAC activity by 48% and HDAC1/2 protein levels by 42% in Npr1+/- mice compared with wild-type mice. Heterozygous Npr1+/- mice exhibited higher systolic blood pressure (SBP, mm Hg) (130 ± 6 vs. Npr1+/+, 102 ± 3 and Npr1++/+ mice, 93 ± 3) and lower creatinine clearance (µl/min) (51 ± 10 vs. Npr1+/+ mice, 130 ± 14; p < 0.05). MGCD-treated Npr1+/- mice showed significantly reduced SBP (106 ± 3; p < 0.001) and increased creatinine clearance (105 ± 13; p < 0.05) compared with vehicle-treated Npr1+/- mice. Higher urinary total protein and albumin to creatinine ratios were also detected in Npr1+/- mutant mice compared with Npr1+/+; however, both of these parameters were dramatically reversed after MGCD treatment.

Conclusion

The present results demonstrate that HDAC inhibitor, MGCD upregulates Npr1 expression in vivo and repairs renal injury in Npr1+/- mice. These findings will have important implications in the treatment and prevention of hypertension and renal injury and dysfunction in humans.

Funding

  • Other NIH Support