Pulmonary arterial hypertension (PAH) isa fatal disease characterized by vascular remodeling and chronic inflammation. Macrophages are the key orchestrators of inflammatory and repair responses, and have been demonstrated to be vital in the pathogenesis of PAH. However, specific phenotype of macrophage polarization (M1 & M2 macrophage) in the development of PAH and the underlying mechanisms how they work are still largely unclear. A rat model of monocrotaline (MCT) induced PAH was used. Hemodynamic analysis and histopathological experiments were conducted at day 3, 7, 14, 21 and 28, respectively. In PAH rat lung tissue, confocal microscopic images showed that CD68+NOS2+ M1-like macrophages were remarkably infiltrated on early stage, but dramatically decreased in mid-late stage. Meanwhile, CD68+CD206+ M2-like macrophages in lung tissue accumulated gradually since day 7 to day 28, and the relative ratio of M2/M1 macrophage increased over time. Results detected by western blot and immunohistochemistry were consistent. Further vitro functional studies revealed the possible mechanism involved in this pathophysiological process. By using Transwell co-culture system, it was found that M1 macrophages inducedendothelial cellapoptosis, while M2 macrophages significantly promoted proliferation of both endothelial cell and smooth muscle cell.These data preliminarily demonstrated a temporal dynamic change of macrophage M1/M2 polarization status in the development of experimental PAH. M1 macrophages participated in the initial stage of inflammation by accelerating apoptosis of endothelial cell, while M2 macrophages predominated in the reparative stage of inflammation and the followed stage of aberrant tissue remodeling.

• MeSH
• Antigens, Differentiation, Myelomonocytic metabolism   MeSH
• Apoptosis MeSH
• Pulmonary Artery metabolism   pathology   MeSH
• Time Factors MeSH
• Antigens, CD metabolism   MeSH
• Cytokines metabolism   MeSH
• Human Umbilical Vein Endothelial Cells metabolism   pathology   MeSH
• Phenotype MeSH
• Coculture Techniques MeSH
• Rats MeSH
• Cells, Cultured MeSH
• Humans MeSH
• Macrophages metabolism   pathology   MeSH
• Inflammation Mediators metabolism   MeSH
• Disease Models, Animal MeSH
• Monocrotaline MeSH
• Myocytes, Smooth Muscle metabolism   pathology   MeSH
• Pulmonary Arterial Hypertension chemically induced   metabolism   pathology   MeSH
• Rats, Sprague-Dawley MeSH
• Cell Proliferation MeSH
• Mannose Receptor metabolism   MeSH
• Vascular Remodeling * MeSH
• Nitric Oxide Synthase Type II metabolism   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Humans MeSH
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Antigens, Differentiation, Myelomonocytic MeSH
• Antigens, CD MeSH
• CD68 protein, rat MeSH Browser
• Cytokines MeSH
• Inflammation Mediators MeSH
• Monocrotaline MeSH
• Nos2 protein, rat MeSH Browser
• Mannose Receptor MeSH
• Nitric Oxide Synthase Type II MeSH

OBJECTIVE: Our previous study in heterozygous Ren-2 transgenic rats (TGR) demonstrated that long-term treatment with endothelin receptor A (ETA) blocker atrasentan added to the renin-angiotensin system (RAS) blockade had renoprotective effects in a model of chronic kidney disease (CKD) induced by partial nephrectomy. Since ETA blockade is known to cause edema, we were interested whether diuretic treatment added to this therapy would be beneficial. DESIGN AND METHODS: Partial nephrectomy (NX) was performed at the age of 3 months in TGR rats which were subjected to: (i) RAS blockade alone (angiotensin receptor blocker losartan and angiotensin converting enzyme inhibitor trandolapril), (ii) combined RAS (losartan and trandolapril) and ETA receptor blockade (atrasentan), or (iii) diuretic (hydrochlorothiazide) added to the combined RAS + ETA blockade for 50 weeks following NX. RESULTS: At the end of the study systolic blood pressure and cardiac hypertrophy were similarly decreased in all treated groups. Survival was significantly improved by ETA receptor blockade added to RAS blockade with no further effects of diuretic treatment. However, additional diuretic treatment combined with RAS + ETA blockade decreased body weight and had beneficial renoprotective effects - reductions of both kidney weight and kidney damage markers. Proteinuria gradually increased in rats treated with RAS blockade alone, while it was substantially lowered by additional ETA blockade. In rats treated with additional diuretic, proteinuria was progressively reduced throughout the experiment. CONCLUSION: A diuretic added to the combined RAS and ETA blockade has late renoprotective effects in CKD induced by partial nephrectomy in Ren-2 transgenic rats. The diuretic improved: renal function (evaluated as proteinuria and creatinine clearance), renal morphology (kidney mass, glomerular volume), and histological markers of kidney damage (glomerulosclerosis index, tubulointerstitial injury).

• Keywords
• atrasentan, chronic kidney disease, hydrochlorothiazide, losartan, nephrectomy, renoprotection, trandolapril,
• Publication type
• Journal Article MeSH