title: The functional and structural changes of the glomerulus throughout the course of murine lupus nephritis.
abstract: The glomerular functional and structural changes in a murine model (MRL-lpr/lpr) of progressive lupus nephritis were studied. Animals were grouped into three age categories. (I, 14 wk; II, 20 wk; and III, 26 wk). GFR fell with age (257 +/- 43, 178 +/- 50, and 150 +/- 40 microL/min for Groups I through III, respectively). Similarly, the ultrafiltration coefficient (Kf) measured on isolated glomeruli fell with time (0.030 +/- 0.006, 0.023 +/- 0.006, and 0.013 +/- 0.002 nL/s/mm Hg, respectively). Both indomethacin and a selective thromboxane receptor antagonist L-670,596 significantly improved GFR in Group II animals to values seen in Group I animals. Neither agent had any effect to increase GFR in older group III animals. L-670,596 had no effect on Kf in Group II or III animals. Glomerular morphometric evaluation demonstrated a progressive rise in glomerular tuft volume, mesangial matrix expansion, proliferation in cells, and a reduction in open capillary loops and epithelial filtration slits with age. However, because of the increase in glomerular volume, calculated surface area remained well preserved over the three respective groups (61 +/- 18, 76 +/- 15, and 71 +/- 13 microns2 x 10(3)). Therefore, the fall in Kf is likely due to a fall in hydraulic permeability (Lp). The ultrastructural component of the glomerular capillary wall that correlated best with Lp was the epithelial filtration slit number per micrometer of glomerular basement length (r = 0.73; P < 0.0001), which suggests that the structural correlate Kf is in the filtration slit length (FSL). Despite the cell proliferation and mesangial matrix expansion in early disease (Group II), the overall FSL remains stable because of a slight increase in filtration surface area and a slight reduction in epithelial slits per micrometer of glomerular basement membrane. The fall in GFR appears to be hemodynamically mediated by thromboxane A2. In older Group III animals, the fall in GFR appears to be due to a 40% reduction in FSL rather than being hemodynamically based. Thus, the early improvement in function with pharmacological agents is deceptive because considerable disease may be present because of adaptive structural changes. Eventually, with disease progression, compensating hemodynamic and structural factors fail to maintain GFR within normal limits.
authors.affiliation: Department of Medicine, Queen's University, Kingston, Ontario, Canada.
authors.forename: B A
authors.initials: BA
authors.lastname: Kiberd
mesh_terms: D015121:6-Ketoprostaglandin F1 alpha / Q000652:urine; D000818:Animals; D001835:Body Weight; D002227:Carbazoles / Q000494:pharmacology; D005260:Female; D005919:Glomerular Filtration Rate; D006400:Hematocrit; D007213:Indomethacin / Q000494:pharmacology; D007678:Kidney Glomerulus / Q000502:physiology* / Q000648:ultrastructure*; D008181:Lupus Nephritis / Q000473:pathology* / Q000503:physiopathology*; D051379:Mice; D008815:Mice, Inbred Strains; D008817:Mice, Mutant Strains; D009929:Organ Size; D012079:Renal Circulation; D013929:Thromboxane B2 / Q000652:urine
chemical_list: D002227:Carbazoles; C061299:L 670596; D013929:Thromboxane B2; D015121:6-Ketoprostaglandin F1 alpha; D007213:Indomethacin