Abstract
The role of podocytes in the development and progression of glomerular disease has been extensively investigated in the past decade. However, the importance of glomerular endothelial cells in the pathogenesis of proteinuria and glomerulosclerosis has been largely ignored. Recent studies have demonstrated that endothelial nitric oxide synthatase (eNOS) deficiency exacerbates renal injury in anti-GBM and remnant kidney models and accelerates diabetic kidney damage. Increasing evidence also demonstrates the importance of the glomerular endothelium in preventing proteinuria. We hypothesize that endothelial dysfunction can initiate and promote the development and progression of glomerulopathy. Administration of adriamycin (ADR) to C57BL/6 mice, normally an ADR resistant strain, with an eNOS deficiency induced overt proteinuria, severe glomerulosclerosis, interstitial fibrosis and inflammation. We also examined glomerular endothelial cell and podocyte injury in ADR-induced nephropathy in Balb/c mice, an ADR susceptible strain, by immunostaining, TUNEL and Western blotting. Interestingly, down-regulation of eNOS and the appearance of apoptotic glomerular endothelial cells occurred as early as 24 hours after ADR injection, whilst synaptopodin, a functional podocyte marker, was reduced 7 days after ADR injection and coincided with a significant increase in the number of apoptotic podocytes. Furthermore, conditioned media from mouse microvascular endothelial cells over-expressing GFP-eNOS protected podocytes from TNF-α-induced loss of synaptopodin. In conclusion, our study demonstrated that endothelial dysfunction and damage precedes podocyte injury in ADR-induced nephropathy. Glomerular endothelial cells may protect podocytes from inflammatory insult. Understanding the role of glomerular endothelial dysfunction in the development of kidney disease will facilitate in the design of novel strategies to treat kidney disease.
Highlights
Diabetic and non-diabetic glomerular diseases remain the major cause of chronic and end-stage renal disease [1]
Immunostaining demonstrated that the production of collagen IV (Fig. 3 A to D & I) and fibronectin (Fig. 3E to H & I) was significantly increased in ADR-treated endothelial nitric oxide synthatase (eNOS)-deficient kidneys compared with normal saline (NS)-treated eNOS-deficient, NS-treated wild type and ADR-treated wild type kidneys
In the present study using two mouse strains C57BL/6, an ADR resistant strain, and Balb/c, an ADR-susceptible strain, we have demonstrated that one of the important factors in driving ADRinduced nephropathy is the level of expression of eNOS. eNOS deficient C57BL/6 mice when treated with ADR developed overt proteinuria, persistent glomerular endothelial cell and podocyte injury, progressive glomerulosclerosis, tubulointerstitial fibrosis and inflammation
Summary
Diabetic and non-diabetic glomerular diseases remain the major cause of chronic and end-stage renal disease [1]. Recent studies have demonstrated that endothelial nitric oxide synthatase (eNOS) deficiency exacerbates renal injury in anti-GBM [6] and remnant kidney models [7] and accelerates diabetic kidney damage with features that resemble human diabetic nephropathy (DN) [8,9,10,11]. Scavengers of endothelial nitric oxide (NO)production, such as asymmetric dimethyl-arginine or N-Nitro-LArginine Methyl Ester (L-NAME) can acutely increase glomerular permeability and induce proteinuria [15,16,17]. These studies suggest that endothelial dysfunction is involved in the development of diabetic and non-diabetic glomerular injury and renal fibrosis [18,19]
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