Heminephrectomy Causes the Progression of Glomerulosclerosis and Apoptosis in High IgA Strain ddY Mice

Abstract

Background: The reduction in nephrons in IgA nephropathy is critical to the prognosis of this disease. However, the immunopathological mechanism of the modifications seen in glomerular lesions is not clear. We thus investigated the influence of nephron reduction by heminephrectomy on renal lesions in a high immunoglobulin A inbred strain of ddY mouse (HIGA mouse), which shows progressive mesangial sclerosis with elevated renal expression of transforming growth factor (TGF)-β. Methods: Five-week-old HIGA mice were heminephrectomized (Nx), and were evaluated in comparison with a sham-operated group (S) at 40 weeks old. Histological findings, immunoglobulin depositions (IgG, IgA, and IgM), and expressions of cytokine and extracellular matrix proteins (TGF-β, fibronectin, collagen type I and IV) were analysed. PCNA and TUNEL stainings were performed with electron microscopic detection of apoptosis. Tissue renin-angiotensin systems (RAS) were also investigated by real-time quantitative RT-PCR. Results: In the Nx group, the glomerular tuft area and ratio of mesangial matrix area per tuft were significantly increased, and the glomerular cell count per tuft area was significantly decreased. Glomerular immunoglobulin deposits of IgG, IgA, and IgM in Nx were all significantly expanded in the paramesangium. The glomerular expressions of TGF-β and the extracellular matrix proteins were significantly increased in Nx mice. In contrast to the significant decrease of PCNA-positive cells, TUNEL-positive cells were significantly increased in Nx. Angiotensin-converting enzyme (ACE) was significantly increased in the renal cortex of Nx. Conclusion: Simple heminephrectomy, other than 5/6 renal ablation, of HIGA mice may be a potential model for research into the progressive glomerulosclerosis of human IgA nephropathy. The pathological role of apoptosis is apparently involved in these disease processes, possibly through upregulated RAS.

Angiotensin II Type 1 Receptor Blockade Inhibits the Development and Progression of HIV-Associated Nephropathy in a Mouse Model

“…Nephron reduction by heminephrectomy is known to enhance glomerular injury in several animal models (21)(22)(23)(24)(25)(26)(27). In this study, using a podocyte-specific transgenic HIVAN mouse line, we demonstrated that removal of one kidney dramatically accelerated podocyte injury and led to severe glomerulosclerosis.…”

“…There was marked progression in renal injury after 8 to 16 wk. In some experimental animal models, heminephrectomy accelerates renal injury (21)(22)(23)(24)(25)(26)(27). To test the hypothesis that nephron reduction enhances podocytes injury and accelerates collapsing glomerulopathy, we heminephrectomized podocin/Vpr mice 1 wk before the administration of doxycycline (Figure 2A).…”

TJN-259 Improves Mesangial Lesions in Experimental Immunoglobulin A Nephropathy in ddY Mice

“…4) Glomerular angiotensin convertase enzyme (ACE) in unilateral nephrectomized mice was significantly enhanced, and this enhancement suggests that the increase in the intraglomerular blood pressure might be caused by the progression of renal damage. 4) However, this study showed that captopril, a representative ACE inhibitor, failed to improve histopathological changes in an accelerated model of IgA nephropathy. Thus, the results suggest that the progression of a model combining unilateral nephrectomy, reticuloendothelial system blockade, and oral administration of bovine g globulin may not depend on intraglomerular hypertension.…”

“…On the other hand, unilateral nephrectomy, blockade of the reticuloendothelial system, and oral sensitization in ddY mice have demonstrated that the deposition of IgA and pathological changes in glomeruli may be induced earlier than those in spontaneous ddY mice. [3][4][5] Transforming growth factor-b1 (TGF-b1) induces matrix synthesis in renal tissues, leading to the progression of IgA nephropathy. 6,7) When added to cultured human mesangial cells, aggregated IgA1 from patients with IgA nephropathy induces increases in TGF-b1 gene expression and secretion of extracellular matrix in cultured mesangial cells.…”

Renal Effects of Coxsackie B4 Virus in Hyper-IgA Mice

“…In addition, the expression of TGF-␤ in the kidney was shown to be increased in these mice (21). Moreover, HIGA mice show a remarkable glomerular deposition of matrix components such as fibronectin and collagen IV (22). These findings suggest that HIGA mice may provide a valuable model for studying the mechanisms of chronic sclerosis developing types of IgAN.…”