Streptokinase as a mediator of acute post-streptococcal glomerulonephritis in an experimental mouse model

Abstract

Group A streptococcal infections are sometimes followed by the inflammatory kidney disease acute post-streptococcal glomerulonephritis (APSGN). To test the importance of streptokinase in the pathogenesis of this disease, isogenic strains of the nephritis isolate NZ131, differing only in the ability to produce streptokinase of the nephritis-associated ska1 genotype, were used for infection in a mouse tissue cage model for APSGN. Streptokinase production was found to be a prerequisite for the capacity of the strain to induce APSGN in mice. In addition, streptokinase was demonstrated in the kidneys of mice infected with the nephritogenic NZ131 and EF514 strains. After infection with the nonnephritogenic strain S84, neither streptokinase nor C3 deposition were observed. Deposition of streptokinase in the glomeruli was detected as soon as 4 days after infection. These findings provide support for the hypothesis that streptokinase initiates the nephritis process by glomerular deposition, which leads to local activation of the complement cascade. Detection of streptokinase in kidney tissue increased with the degree of glomerular hypercellularity. Thus, the severity of the pathological process may be a reflection of the degree of streptokinase deposition.

FIG. 1

Kidney sections of glomeruli stained with hematoxylin and periodic acid Schiff. The mice were treated with penicillin from day 7 p.i. (A) Kidney section from mouse infected with NZ131. The glomerulus was considered positive for hypercellularity, occlusion of capillaries, and lobulation. (B) Kidney section from mouse infected with the streptokinase-defective Em^r isogenic derivative of NZ131. This glomerulus was regarded as negative for morphological signs of APSGN. Magnification, ×650.

FIG. 2

Kidney sections of glomeruli with immunofluorescent staining for C3. The mice were treated with penicillin from day 16 p.i. (A and B) Kidney sections from mice infected with NZ131. These glomeruli were regarded as positive for C3 deposition, with granular deposits along capillary walls and partially blurred boundaries in the mesangium equivalent to the so-called mesangial pattern (26). (C) Kidney section from mouse infected with strain NZ131 from which the streptokinase gene was deleted. This glomerulus was regarded as negative for C3 deposition. Magnification, ×650.

FIG. 2

Kidney sections of glomeruli with immunofluorescent staining for C3. The mice were treated with penicillin from day 16 p.i. (A and B) Kidney sections from mice infected with NZ131. These glomeruli were regarded as positive for C3 deposition, with granular deposits along capillary walls and partially blurred boundaries in the mesangium equivalent to the so-called mesangial pattern (26). (C) Kidney section from mouse infected with strain NZ131 from which the streptokinase gene was deleted. This glomerulus was regarded as negative for C3 deposition. Magnification, ×650.

FIG. 3

Streptokinase deposition was demonstrated in glomeruli and tubuli of mice infected with the nephritogenic strains NZ131 and EF514. Glomerular sites for streptokinase deposition are here exemplified with tissue from an EF514-infected mouse which had been treated with penicillin from day 7 p.i. The protein was detected along the basement membrane, in the mesangium (A), and in the capsular epithelium layer (B). Immunogold-silver acetate autometallography method was used with eosin as counterstain. Magnification, ×1,000.