Ralf Bernd Sterzel

Transforming growth factor-β in renal disease

An extensive number of animal and clinical studies indicate that transforming growth factors-β (TGF-βs) play an important role in inflammatory and fibrotic diseases, including renal fibrosis. Recent mouse models harboring genetically engineered alterations in TGF-β pathways reveal complicated mechanisms of regulation of TGF-β activity in vivo. The purpose of this review is to present recent advances relevant to our understanding of the TGF-β-signaling system in renal physiology and pathophysiology.

Vasoactive Diadenosine Polyphosphates Promote Growth of Cultured Renal Mesangial Cells

Diadenosine polyphosphates (diadenosine triphosphate, Ap3A; diadenosine tetraphosphate, Ap4A; diadenosine pentaphosphate, Ap5A; diadenosine hexaphosphate, Ap6A) are potent vasoactive molecules stored and released by platelets. We examined whether these dinucleotides might contribute to the glomerular inflammatory response by stimulating the proliferation of mesangial cells. In cultured rat mesangial cells all four tested dinucleotides (10 to 100 mumol/L) significantly stimulated DNA synthesis as measured by [3H]thymidine uptake at 48 hours (x-fold increase compared with unstimulated control cells: Ap3A, 1.5; Ap4A, 1.8; Ap5A, 1.6; Ap6A, 1.6). In combination with the platelet products platelet-derived growth factor, epidermal growth factor, and serotonin, the dinucleotides synergistically increased DNA synthesis. Dinucleotides by themselves increased cell counts by 23% to 43% at day 2 and augmented mesangial cell growth induced by platelet-derived growth factor, epidermal growth factor, and serotonin. Furthermore, dinucleotides (100 mumol/L) rapidly induced a modest increase in expression of the early growth response gene Egr-1 at 30 minutes (x-fold increase over baseline control: Ap3A, 1.9; Ap4A, 2.8; Ap5A, 2.2; Ap6A, 2.1). We found that extracellular Ap4A was metabolized by mesangial cell ectoenzymes to mononucleotides and adenosine, which also have been shown to be mitogenic for mesangial cells. The combination of Ap4A with mononucleotides or adenosine failed to cause additive stimulation of DNA synthesis in mesangial cells. We conclude that diadenosine polyphosphates stimulate proliferation of cultured mesangial cells and augment mesangial cell growth induced by other mitogens released from platelets. Different molecular mechanisms may be involved in dinucleotide-induced mitogenesis of mesangial cells. Direct effects of dinucleotides on cultured mesangial cells. Direct effects of dinucleotides on cultured mesangial cells appear to play a role because dinucleotides rapidly caused activation of Egr-1.(ABSTRACT TRUNCATED AT 250 WORDS)

Mesangial Cells and Their Adhesive Properties

Glomerular mesangial cells play a central role in maintaining structure and function of the glomerular capillary ultrafiltration apparatus. Under physiological and pathological conditions, mesangial cells regulate amount and composition of the surrounding extracellular matrix. Conversely, components of the embedding matrix affect the mesangial cell phenotype. These interactions are mediated via specific cell surface receptors, the best studied group of which is the β1 integrin family. The β1 integrins play a role in mesangial cell adhesion, migration, survival and proliferation. Expression and abundance of integrins in healthy and diseased glomeruli and their functions and mediation of signals are discussed in this review. Other factors modulating mesangial cell-matrix interactions, such as antiadhesive proteins, cytokines, disintegrins and nitric oxide, are also considered. The available evidence from in vitro and in vivo studies indicates that receptor-mediated interactions between mesangial cells and the normal or abnormal extracellular matrix regulate the mesangial cell phenotype and thus contribute to normal maintenance of the glomerulus and to remodeling and repair of the glomerular capillary tuft in response to injury.