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A Modified Two Kidney One Clip Mouse Model of Renin Regulation in Renal Artery Stenosis
Published on: October 26, 2020
Angiotensin receptor blockade attenuates glomerulosclerosis progression by promoting VEGF expression and bone
Shu-min Song1, Cen-cen Wang, Si-hua Qi
1Department of Nephrology, 2nd Affiliated Hospital, and Department of Pharmacology, Harbin Medical University, Harbin, People’s Republic of China.
Insights
Angiotensin receptor blockers like valsartan promote kidney repair by recruiting bone marrow cells that express VEGF, improving kidney function and reducing glomerulosclerosis. This study clarifies the mechanisms behind ARB-mediated glomerular healing.
Area of Science:
- Nephrology
- Regenerative Medicine
- Pharmacology
Background:
- Angiotensin Type I receptor blockade (ARB) is known to reduce proteinuria and glomerular injury.
- The precise cellular and molecular mechanisms underlying ARB's renoprotective effects, particularly concerning bone marrow cell involvement, remain unclear.
- This study investigates the role of bone marrow-derived cells in glomerular repair during ARB treatment.
Purpose of the Study:
- To investigate the role of bone marrow-derived cells (BMDCs) in glomerular repair during angiotensin receptor blockade (ARB).
- To elucidate the cellular and molecular mechanisms by which ARB, specifically valsartan, promotes kidney healing in a rat model of progressive glomerulosclerosis.
Main Methods:
- Progressive glomerulosclerosis was induced in enhanced green fluorescent protein (GFP) bone marrow chimeric rats using anti-Thy 1.1 antibody and unilateral nephrectomy.
- Rats received either valsartan or no treatment from weeks 2 to 8 post-disease induction.
- Renal function, proteinuria, and histological changes were assessed at 8 weeks.
Main Results:
- Valsartan treatment significantly improved renal function, reduced glomerulosclerosis severity, and decreased mortality.
- Valsartan enhanced glomerular tuft regeneration, lowered proteinuria, and increased vascular endothelial growth factor (VEGF) expression.
- Valsartan promoted the recruitment of BMDCs to the glomerulus, many expressing VEGF and CD68, suggesting a role in repair.
Conclusions:
- Angiotensin receptor blockade with valsartan prevents glomerulosclerosis progression by enhancing glomerular capillary repair.
- This repair process involves the recruitment of VEGF-producing, reparative monocytes and macrophages from the bone marrow.
- The findings highlight the contribution of BMDCs to ARB-mediated renoprotection.
Background:
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.
Methods:
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.
Results:
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.
Conclusions:
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.
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