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Pentoxifylline attenuates experimental mesangial proliferative glomerulonephritis
Y M Chen1, C T Chien, M I Hu-Tsai
1Department of Medicine, National Taiwan University Hospital, Taipei, Taiwan.
Background:
Accumulation of glomerular macrophages, proliferation of mesangial cells (MCs), and deposition of extracellular matrix proteins are pathobiological hallmarks of glomerulonephritis. We previously reported that a clinically available nonselective inhibitor of cyclic 3',5'-nucleotide phosphodiesterase, pentoxifylline (PTX), inhibits proliferation of cultured rat MCs, as well as collagen production by these cells. In this study, we investigated the in vivo effects of PTX on rat anti-Thy1 disease, a model of mesangial proliferative nephritis.
Methods:
Anti-Thy1 nephritis was induced in Sprague-Dawley rats by injecting mouse anti-rat Thy1 antibodies intravenously. Nephritic rats were randomly assigned to receive PTX (0.1 g/kg/day) or vehicle (phosphate-buffered saline) and were sacrificed at various time points. Paraffin kidney sections were stained with hematoxylin and periodic acid-Schiff reagents for glomerular histology. Frozen kidney sections were stained by monoclonal antibodies against proliferating cell nuclear antigen, ED-1, and alpha-smooth muscle actin and were visualized by color development from a horseradish peroxidase reaction. Monocyte chemoattractant protein-1 (MCP-1), intercellular adhesion molecule-1 (ICAM-1), and various extracellular matrix mRNAs were analyzed by Northern blotting. Urine protein concentrations were determined by Lowry's method.
Results:
Nephritic rats treated with PTX excreted less urinary protein on day 5 of nephritis than vehicle-treated nephritic rats. In periodic acid-Schiff-stained kidneys from PTX-treated nephritic rats, there was attenuation of both glomerular cellularity and glomerular sclerosis compared with vehicle-treated nephritic rats. PTX decreased the augmented glomerular mRNA levels of MCP-1 and ICAM-1 at two hours and on day 1 of nephritis. Immunoreactive staining showed that PTX reduced the number of proliferating glomerular macrophages on days 1, 2, and 3, but not at two hours of nephritis, compared with vehicle-treated nephritic rats. On day 5, PTX decreased the number of activated proliferating MCs and attenuated the glomerular mRNA levels of type I (alpha1), type III (alpha1), and type IV (alpha1) collagen and fibronectin compared with vehicle-treated nephritic rats.
Conclusion:
The administration of PTX to rats with anti-Thy1 disease reduces accumulation and proliferation of glomerular macrophages, attenuates proteinuria, suppresses activation and proliferation of MCs, and ameliorates glomerular sclerosis. These results suggest that PTX may have a suppressive effect in acute phases or relapses of mesangial proliferative glomerulonephritis.
Insights
Pentoxifylline (PTX) treatment in rats with anti-Thy1 nephritis reduced glomerular macrophage accumulation and proliferation, and mesangial cell activation. This led to attenuated proteinuria and ameliorated glomerular sclerosis, suggesting PTX may help treat mesangial proliferative glomerulonephritis.
Area of Science:
- Nephrology
- Immunology
- Pharmacology
Background:
- Glomerulonephritis is characterized by glomerular macrophage accumulation, mesangial cell proliferation, and extracellular matrix deposition.
- Pentoxifylline (PTX), a phosphodiesterase inhibitor, previously showed in vitro inhibition of rat mesangial cell proliferation and collagen production.
- This study investigated the in vivo efficacy of PTX in a rat model of mesangial proliferative nephritis (anti-Thy1 disease).
Purpose of the Study:
- To evaluate the therapeutic effects of pentoxifylline (PTX) on established anti-Thy1 nephritis in rats.
- To assess PTX's impact on key pathological features including glomerular macrophages, mesangial cells, and extracellular matrix.
- To determine if PTX can reduce proteinuria and glomerular sclerosis in this nephritis model.
Main Methods:
- Anti-Thy1 nephritis was induced in rats, followed by random assignment to PTX or vehicle treatment.
- Kidney tissues were analyzed for histology, cellularity, sclerosis, and expression of markers for proliferation (PCNA), macrophages (ED-1), and activated cells (alpha-SMA).
- Glomerular mRNA levels of MCP-1, ICAM-1, collagens, and fibronectin were quantified, alongside urinary protein excretion.
Main Results:
- PTX treatment significantly reduced urinary protein excretion and attenuated glomerular cellularity and sclerosis.
- PTX decreased glomerular mRNA levels of MCP-1 and ICAM-1, and reduced the accumulation/proliferation of glomerular macrophages.
- PTX suppressed mesangial cell activation/proliferation and attenuated the expression of type I, III, and IV collagen and fibronectin on day 5 of nephritis.
Conclusions:
- Pentoxifylline (PTX) administration ameliorates key pathological features of anti-Thy1 glomerulonephritis in rats.
- PTX effectively reduces glomerular macrophage and mesangial cell proliferation and extracellular matrix deposition.
- These findings suggest PTX holds potential for managing acute phases or relapses of mesangial proliferative glomerulonephritis.