Cyclic stretching of mesangial cells up-regulates intercellular adhesion molecule-1 and leukocyte adherence - A possible new mechanism for glomerulosclerosis

Intraglomerular hypertension is a primary causal factor in the progressive glomerulosclerosis that characterizes diabetic nephropathy or severe renal ablation. However, inflammation of the glomerular mesangium also participat es in at least the early phase of these diseases. in glomerulonephritis, wh ere inflammation is thought to be the predominant causal factor, intraglome rular hypertension is also often present. Mesangial cells (MCs) are critica l in orchestrating key functions of the glomerulus including extracellular matrix metabolism, cytokine production, and interaction with leukocytes, Be cause MCs are subject to increased stretching when intraglomerular hyperten sion is present, and in glomerulonephritis MC/ leukocyte interactions seem to be mediated primarily via the up-regulation of intercellular adhesion mo lecule-1 (ICAM-1), we examine the possibility that cyclic stretching is a s timulus for increased MC ICAM-1 activity. We demonstrate that the normal lo w levels of MC ICAM-1 mRNA and protein are dramatically upregulated by even short intervals of cyclic stretch. This effect is dose- and time-dependent , and requires little amplitude and a brief period of elongation for signif icant induction. Stretch-induced MC ICAM-1 also leads to a marked elevation in phagocytic leukocyte adherence. This stimulated adherence is equal or g reater than that induced by the inflammatory cytokine tumor necrosis factor -alpha, whereas an additive effect occurs when both are applied in combinat ion. Our results indicate that stretch-induced ICAM-1 may provide a direct link between hypertension and inflammation in the progression of injury and glomerulosclerosis in diabetes, renal ablation, and other forms of glomeru lonephritis.