Extracellular matrix expansion is frequently noted in mesangioproliferative renal diseases. This study investigates the role of immunologic factors in glomerular matrix accumulation. The gene expression of type I and IV collagen, laminin and s-laminin was examined in the rat model of mesangial proliferative glomerulonephritis induced with anti-Thy 1.1 antibody. Northern analysis was performed on glomerular RNA isolated one, three and five days after disease induction and at day 3 following prior complement depletion. Tissue was immunostained for the protein products of these genes as well as for heparan sulfate proteoglycan, entactin and PCNA (a marker of cell proliferation) at days 1, 3, 5, 14, 21 and 42. A seven- to ten-fold increase of collagen IV and laminin mRNA as well as de novo expression of collagen I mRNA occurred at days 3 and 5 corresponding to the time of maximal proliferation. S-laminin mRNA levels only increased three-fold. With the exception of s-laminin, mesangial staining for all examined matrix proteins increased to a maximum at day 5 and decreased thereafter. Focal alterations of the glomerular architecture and matrix persisted at day 42. Complement depletion prevented the histological abnormalities as well as the increased expression of matrix proteins at day 3. These findings indicate that immunologic injury in the mesangium may result in overproduction of extracellular matrix components and may ultimately contribute to the development of glomerulosclerosis.

A B S T R A C T Detailed studies were undertaken to better define the role of the liver and the folate enterohepatic cycle in folate homeostasis.

Chronic progressive membranous nephropathy (MN) in humans is characterized by thickening of the glomerular basement membrane (GBM) with formation of spikes which contain laminin and other extracellular matrix (ECM) proteins. We have utilized two models of MN in the rat (active and passive Heymann nephritis, AICN, PHN) to define the sequential changes in composition of GBM as they relate to changes in glomerular gene expression for ECM components, altered permeability and morphological changes. Renal biopsies obtained during the course of AICN and PHN were immunostained for various ECM proteins and total glomerular RNA was hybridized with cDNA probes specific for laminin B2-chain, s-laminin, and types I and IV collagen. In addition, the ability of anti-glomerular epithelial cell (GEC) antibody and complement on rat GEC in culture to induce laminin release or laminin and s-laminin mRNA expression was determined. The results demonstrate that at weeks 12, 16, and 20 of AICN, immunostaining for laminin, s-laminin, fibronectin, entactin, and heparan sulfate proteoglycan increased in the GBM in a spike-like pattern. Concomitantly, glomerular mRNA levels of laminin B2-chain and of s-laminin increased. Type IV collagen protein and gene expression remained unchanged or decreased. No glomerular immunostaining for type I collagen occurred during AICN despite increased expression of mRNA for this collagen type. In contrast to AICN, in PHN no pronounced changes of the glomerular ECM occurred, except for transient expression of type I collagen mRNA in whole glomerular RNA and type I collagen protein the GEC cytoplasm. Stimulation of GEC in culture with anti-GEC antibody and complement also failed to induce transcription of laminin or s-laminin mRNA or the release of laminin protein. These findings suggest that the polyantigenic expansion of GBM which occurs in chronic experimental MN may be stimulated by factors different from the C5b-9 mediated processes that cause the initial proteinuria.

After exercise the lactate (La) removal from blood occurs significantly faster during moderate exercise than at rest. However, under both conditions there are considerable inter-individual differences in La removal. These differences in man may depend on the slow-twitch (ST) fiber content of muscle (X1), the La concentration in blood (X2), and the intensity of the recovery exercise (X3). Therefore, multiple regression models were obtained to describe La removal rates with these variables. In 10 women La concentrations were increased via a 6 min bicycle ergometer ride (87% VO2max) and blood La concentrations were measured every 5 min during 20 min resting and active recovery periods (29--49% VO2max). For resting recovery only the initial La concentration after the 6 min exercise provided a significant description for La removal in 8 subjects (P = 0.03). However, for the active recovery a highly significant description for La removal was obtained: La removal rate (mM/1 . min) = 0.773 x 10-2X1 + 0.321 x 10-1X2 - 0.120 x 10-1X3 + 0.202 (R = 0.91; P = 0.01). The statistical independence (P greater than 0.010) of each of these variables in the model suggests that each is contributing uniquely to the total removal rate of La observed during an active recovery period. The relationship between La removal and %ST fibers may be related to the metabolic and anatomical features of these fibers, the La concentration probably reflects the significance of the mass action effect of La, and the intensity of exercise reflects the role of the muscle's metabolic rate. The present results illustrate that the removal of blood lactate is influenced by the interactive effects of the intensity of the recovery exercise, blood lactate concentration and the ST fiber content of muscle.

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