Angiotensin receptor blockade attenuates glomerulosclerosis progression by promoting VEGF expression and bone marrow-derived cells recruitment

• Published in: Nephrology, dialysis, transplantation dialysis, transplantation, 2012-07, Vol.27 (7), p.2712-2719
• Main Authors: SONG, Shu-Min, WANG, Cen-Cen, QI, Si-Hua, LI XING, YANG, Bao-Feng, OITE, Takashi, BING LI
• Format: Article
• Language: English
• Subjects: Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Angiotensin Receptor Antagonists - therapeutic use; Animals; Biological and medical sciences; Blotting, Western; Bone Marrow - drug effects; Bone Marrow - metabolism; Bone Marrow - pathology; Bone Marrow Transplantation; Disease Progression; Emergency and intensive care: renal failure. Dialysis management; Female; Fluorescent Antibody Technique; Glomerulonephritis; Glomerulosclerosis, Focal Segmental - metabolism; Glomerulosclerosis, Focal Segmental - pathology; Glomerulosclerosis, Focal Segmental - prevention & control; Green Fluorescent Proteins - genetics; Green Fluorescent Proteins - metabolism; Immunoenzyme Techniques; Intensive care medicine; Isoantibodies - pharmacology; Kidney Glomerulus - cytology; Kidney Glomerulus - drug effects; Kidney Glomerulus - metabolism; Male; Medical sciences; Nephrectomy; Nephrology. Urinary tract diseases; Nephropathies. Renovascular diseases. Renal failure; Rats; Rats, Sprague-Dawley; Rats, Transgenic; Receptors, Angiotensin - chemistry; Tetrazoles - therapeutic use; Thy-1 Antigens - immunology; Valine - analogs & derivatives; Valine - therapeutic use; Valsartan; Vascular Endothelial Growth Factor A - metabolism
• ISSN: 0931-0509; 1460-2385
• DOI: 10.1093/ndt/gfr621

Previous studies have demonstrated that angiotensin Type I receptor blockade (ARB) reduces proteinuria, reverses glomerular injury and glomerulosclerosis in rat models of diabetic nephropathy and glomerulonephritis. However, the cellular and molecular mechanisms are unclear. To investigate the role of cells of the bone marrow (BM) in glomerular repair seen during ARB administration, we induced progressive glomerulosclerosis in enhanced green fluorescent protein BM chimeric rats by a single injection of anti-Thy 1.1 monoclonal antibody, followed by unilateral nephrectomy. Cohorts of rats received valsartan or no treatment from Week 2 to Week 8 after induction of disease. Renal function, urinary protein excretion and histological changes were examined 8 weeks after anti-Thy-1.1 monoclonal antibody injection. Valsartan administration improved renal function, reduced severity of glomerulosclrosis and markedly reduced mortality. Valsartan administration promoted regeneration of the glomerular tuft, lowered proteinuria and resulted in enhanced vascular endothelial growth factor (VEGF) expression in the cortex and glomerular tuft. In addition, valsartan promoted increased recruitment of BM-derived cells (BMDCs) many of which expressed VEGF and likely contributed directly to glomerular repair. Nearly all BMDCs recruited to the glomerulus expressed the monocyte/macrophage marker CD68. In conclusion, the data shows that ARB by valsartan prevents glomerulosclerosis progression by enhancing glomerular capillary repair which is associated with the recruitment of VEGF producing 'reparative' monocytes and macrophages from the BM.