Renoprotective action of a matrix metalloproteinase inhibitor in progressive mesangioproliferative nephritis.

BACKGROUND/AIM: Matrix metalloproteinases (MMPs) play pivotal roles in extracellular matrix turnover and are involved in chronic kidney disease. The renoprotective action of a synthetic MMP inhibitor, compound A, was investigated in chronic nephritis. METHODS: Nephritis was induced by a single injection of anti-Thy1.1 antibody to unilaterally nephrectomized rats. The effects of compound A on proteinuria, blood urea nitrogen, and matrix-related gene expressions were evaluated. Collagen accumulation, as assessed by periodic acid-Schiff staining and hydroxyproline content, was determined. The integrity of glomerular epithelial cells and glomerular basement membrane was evaluated with desmin immunohistochemistry and electron microscopic detection of anionic charge sites, respectively. RESULTS: Treatment with compound A notably attenuated proteinuria, ameliorated blood urea nitrogen, and prevented glomerulosclerosis. Gene upregulation of collagen and transforming growth factor ß1 in the cortex was prevented in the treated animals. Glomerular epithelial cell injury was milder, and glomerular basement membrane anionic sites were protected with the treatment. CONCLUSION: A novel MMP inhibitor, compound A, exerts protective effects in progressive glomerulonephritis. Compound A ameliorates various aspects of renal injuries and may have therapeutic potential toward kidney diseases.

Altered expression of matrix-related molecules in the development of chronic Thy1.1 nephritis.

BACKGROUND/AIM: Matrix production and degradation are critically important in chronic nephritis. Our aim was to investigate the precise expression of matrix-related molecules which is essential for understanding the pathogenesis of renal disease. METHODS: Chronic nephritis was induced by a single injection of anti-Thy1.1 antibody to unilaterally nephrectomized rats. RNA was extracted from renal cortex and isolated glomeruli 4, 7, and 10 weeks after the antibody injection. Matrix-related gene expressions were measured by polymerase chain reaction. The expression of alpha1(IV) and alpha3(IV) collagens was studied by immunohistochemistry. The gelatinolytic activity in the glomeruli was assayed by gelatin zymography. RESULTS: Polymerase chain reaction revealed an increase of alpha1(IV) in both glomeruli and renal cortex from nephritic rats. In contrast, the expression of alpha3(IV), normally a component of the glomerular basement membrane, was decreased in nephritic animals. Immunohistochemistry confirmed the finding that alpha1(IV) and alpha3(IV) were up- and downregulated, respectively, in the glomeruli. Gene expression and activity of matrix metalloproteinase 2 were enhanced, while those of matrix metalloproteinase 9 were clearly suppressed in nephritis. CONCLUSIONS: Downregulation of alpha3(IV) and enhancement of the matrix metalloproteinase-2 activity in the glomeruli may contribute to the glomerular damage by altering the glomerular basement membrane components. Impairment of the glomerular basement membrane integrity may possibly be implicated in irreversible renal dysfunction.

Hypotensive and prophylactic effects of angiotensin II subtype 1 receptor antagonist, irbesartan, in stroke-prone spontaneously hypertensive rats.

We determined the acute hypotensive effect of a single administration and the prophylactic effect of chronic treatment with Irbesartan, an angiotensin II receptor antagonist, on the development of end-organ damage in stroke-prone spontaneously hypertensive rats (SHRSP). The acute hypotensive effect was determined by a telemetrical method in SHRSP fed a normal diet. The prophylactic effect was examined by biochemical, histopathological and immunohistochemical methods in SHRSP fed a high-salt and low-protein diet. Irbesartan (3, 10, 30 and 100 mg/kg) reduced blood pressure in a dose-dependent manner without affecting heart rate. Irbesartan (3, 10 and 30 mg/kg) increased the survival rate in SHRSP fed a high-salt and low-protein diet. Furthermore, Irbesartan ameliorated the appearance of stroke symptoms in dose-dependent manner showing association with the prevention of microscopic lesions. Irbesartan ameliorated the increases in urinary protein excretion and N-acetyl-D-glucosamidase activity by preventing nephrosclerosis, as judged by microscopic observations, and ameliorated the increases in the expression of collagen IV and fibronectin in the kidney. These findings demonstrate that Irbesartan is a potent antihypertensive drug offering a protective effect on the development of hypertension-induced end-organ damages in SHRSP. Thus, Irbesartan is useful for the therapy of hypertension with end-organ damage.