Pressure Oscillation Regulates Human Mesangial Cell Growth and Collagen Synthesis

Abstract

Abstract-Experimental renal disease models establish glomerular hypertension as a crucial determinant in glomerulosclerosis progression and demonstrate that glomerular capillary pressure reduction delays sclerosis development. An oscillating pressure (OP) chamber was constructed as an in vitro model to study human mesangial cells. Cell cultures were grown under atmospheric pressure (AP) and a controlled OP corresponding to intraglomerular capillary pressure. We show that OP significantly decreases mesangial cell proliferation within 24 hours and attenuates DNA synthesis throughout a 7-day period. To explore the effects of OP on cell metabolism, cell-associated and medium-secreted extracellular (CA and EC, respectively) collagen synthesis were measured by [ 3 H]proline incorporation. In subconfluent cultures, total CA and EC collagen synthesis was unaffected by OP, while in confluent cultures total EC collagen [ 3 H]proline incorporation was increased. To determine whether OP influenced mesangial cell growth induction, the effects of increasing glucose in the cell culture media were investigated. Our data show that the high glucose growth stimulatory effect on cell number and DNA synthesis was suppressed by OP. Under high glucose conditions, total CA collagen synthesis was increased in confluent cultures, whereas the EC collagen fraction remained unchanged. In these cultures, OP caused an additional increase in CA collagen synthesis. This study shows that mesangial cell growth and collagen synthesis are influenced by hyperbaric OP, supporting the hypothesis that glomerular capillary pressure plays a role in progressive glomerulosclerosis development. 1-4 Experimental models have shown that changes in intracapillary pressure are accompanied by a loss of afferent arteriole glomerular capillary pressure autoregulation.5 Furthermore, therapeutic interventions with angiotensin-converting enzyme inhibitors and low protein diets that reduce glomerular intracapillary pressure can attenuate progression of glomerulosclerosis.6,7 Nevertheless, compelling evidence has not yet been collected about the direct pathophysiologic effects of glomerular intracapillary pressure on intrinsic glomerular cells.A stretch/relaxation model (eg, by cyclic stretch/relaxation of culture plate undersurfaces) has been developed from observations of isolated glomeruli, in which glomerular volume progressively increases with enhanced perfusion pressure. 8 -10 In such studies, shear forces profoundly affect mesangial cell (MC) growth, matrix synthesis, and intermediary filament distribution. 8,9,[11][12][13] However, fixed mesangial compartment expansion and glomerular hypertrophy are commonly found only in advanced stages of glomerulosclerosis, while intraglomerular pressure elevation generally precedes these changes.Mesangial structures with inherent centripetal forces are maintained by specific MC properties, including a smooth muscle cell phenotype, contractility, and contact points with the capillary basal membrane.14 Furthermore, the unique...

Antihypertensive therapy and progression of chronic renal disease

“…In this system under basal culture conditions, total collagen production by mesangial cells was unaffected by high pressure; however, collagen accumulation increased when cells were exposed to both high pressure and a high glucose concentration, as might occur in a diabetic patient with hypertension [9]. This finding is similar to that of Riser et al [10] who reported that the combination of a high glucose concentration and cyclic stretch increased TGF-␤ secretion and collagen accumulation by mesangial cells.…”

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“…Rat mesangial cells were established as previously described [52,53]. Human monocytic THP-1 as well as human breast adenocarcinoma MCF-7 (Michigan Cancer Foundation-7) cells were obtained from the ATCC.…”

Transcription Factor YB-1 Mediates DNA Polymerase α Gene Expression

“…Rat mesangial cells (MCs) were established and characterized as described previously (15,16) and were grown in RPMI 1640 medium supplemented with 10% fetal calf serum, 2 mM L-glutamine, 100 g/ml streptomycin, and 100 units/ml penicillin at 37°C in humidified 5% CO 2 in air. HK-2 cells were maintained as described previously (17).…”