Renal injury in DOCA-salt hypertensive C5-sufficient and C5-deficient mice

Abstract

We induced hypertension by uninephrectomy and treatment with desoxycorticosterone (DOCA) and 1% NaCl in the drinking water in congenic mice that differ in the single gene locus responsible for the presence or absence of the complement component C5 and compared them to uninephrectomized normotensive (no DOCA-NaCl) mice. In contrast to C5-sufficient (C5S) mice. C5-deficient (C5D) mice can neither generate C5a nor assemble C5b-9. After four weeks of treatment, DOCA-C5S and -C5D mice developed similar degrees of hypertension; mice receiving no DOCA remained normotensive. Only hypertensive mice developed glomerular injury. Hypertensive DOCA-C5D mice developed more glomerular capillary loop dilatation and larger glomerular capillary tuft volumes than DOCA-C5S mice (1.0 +/- 0.1 vs. 0.7 +/- 0.03 X 10(6) microns 3, respectively, P less than 0.05). However, DOCA-C5S mice, compared to DOCA-C5D mice, had significantly more glomerular cell proliferation (64.5 +/- 2 vs. 42 +/- 3 nuclei/glomerulus), cell necrosis (injury score 22 +/- 1 vs. 17 +/- 1), extracapillary proliferation (26 +/- 4 vs. 2.5 +/- 2% of glomeruli) and proteinuria (5.9 +/- 0.8 vs. 3.7 +/- 0.5 mg/24 hr; all P less than 0.05). By immunofluorescence microscopy both DOCA-C5S and -C5D had mesangial C3 deposits but only DOCA-C5S mice had C9 deposits. After 16 weeks of DOCA-NaCl C5S mice, in comparison to C5D mice, had more severe glomerulosclerosis (injury score 50 +/- 6 vs. 12 +/- 4), proteinuria (16.6 +/- 0.1 vs. 9 +/- 0.1 mg/24 hr), and renal insufficiency (serum creatinine 0.25 vs. 0.15 mg/dl), all P less than 0.05. These changes occurred despite levels of hypertension that were similar in DOCA-NaCl C5S and C5D throughout the whole study period. We conclude that C5a and/or C5b-9 may play an important role in hypertensive glomerular injury. Moreover, these studies demonstrate that differences in host responses may determine target organ susceptibility to similar injurious mechanisms.