Renoprotective Effect of the Histone Deacetylase Inhibitor CG200745 in DOCA-Salt Hypertensive Rats.

Abstract

The novel histone deacetylase inhibitor CG200745 was initially developed to treat various hematological and solid cancers. We investigated the molecular mechanisms associated with the renoprotective effects of CG200745 using deoxycorticosterone acetate (DOCA)-salt hypertensive (DSH) rats. DOCA strips (200 mg/kg) were implanted into rats one week after unilateral nephrectomy. Two weeks after DOCA implantation, DSH rats were randomly divided into two groups that received either physiological saline or CG200745 (5 mg/kg/day) for another two weeks. The extent of glomerulosclerosis and tubulointerstitial fibrosis was determined by Masson's trichrome staining. The renal expression of fibrosis and inflammatory markers was detected by semiquantitative immunoblotting, a polymerase chain reaction, and immunohistochemistry. Pathological signs such as glomerulosclerosis, tubulointerstitial fibrosis, increased systolic blood pressure, decreased creatinine clearance, and increased albumin-to-creatinine ratios in DSH rats were alleviated by CG200745 treatment compared to those manifestations in positive control animals. Furthermore, this treatment counteracted the increased expression of αSMA, TGF-β1, and Bax, and the decreased expression of Bcl-2 in the kidneys of DSH rats. It also attenuated the increase in the number of apoptotic cells in DSH rats. Thus, CG200745 can effectively prevent the progression of renal injury in DSH rats by exerting anti-inflammatory, anti-fibrotic, and anti-apoptotic effects.

• Authors: Eun Hui Bae, In Jin Kim, Ji Hong Song, Hong Sang Choi, Chang Seong Kim, Gwang Hyeon Eom, Inkyeom Kim, Hyunju Cha, Joong Myung Cho, Seong Kwon Ma, Soo Wan Kim
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 20 Issue 3 (Jan 25 2019) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 30691015 (Publication Type: Journal Article)

Chemical References

• Acta2 protein, rat
• Actins
• Albumins
• Biomarkers
• Histone Deacetylase Inhibitors
• Hydroxamic Acids
• N1-(3-(dimethylamino)propyl)-N8-hydroxy-2-((naphthalene-1-loxy)methyl)oct-2-enediamide
• Naphthalenes
• Tgfb1 protein, rat
• Transforming Growth Factor beta1
• Desoxycorticosterone Acetate
• Creatinine

Topics

• Actins (metabolism)
• Albumins (metabolism)
• Animals
• Apoptosis (drug effects)
• Biomarkers (metabolism)
• Creatinine (metabolism)
• Desoxycorticosterone Acetate (adverse effects)
• Disease Models, Animal
• Histone Deacetylase Inhibitors (administration & dosage, pharmacology)
• Hydroxamic Acids (administration & dosage, pharmacology)
• Hypertension (chemically induced, complications, drug therapy)
• Kidney Diseases (metabolism, prevention & control)
• Male
• Naphthalenes (administration & dosage, pharmacology)
• Random Allocation
• Rats
• Rats, Sprague-Dawley
• Transforming Growth Factor beta1 (metabolism)