Cellular Biology of Glomerulosclerosis

Hypercoagulability, Intraglomerular Coagulation, and Thromboembolism in Nephrotic Syndrome

“…Namely, thrombin can act as a potent stimulus in mesangial cell activation and proliferation, eventually resulting in glo merular sclerosis [88][89][90].…”

“…Platelet activation and localization to the glomeruli can reduce the glomerular filtration rate by generation of thromboxane [91,92], induce local vasoconstriction or capillary occlusion [91,93], increase glomerular perme ability following charge barrier neutralization by a gran ule cationic products [94], and induce mesangial cells to proliferate through the secreted growth factors, resulting in glomerulosclerosis [89,90].…”

“…The neutralization of negatively charged heparan sul fate proteoglycans by platelet-release basic products, namely |3-thromboglobulin and platelet factor 4, at the level of mesangium deserves particular concern, as hepa ran sulfates normally prevent proliferation of mesangial cells and hinder collagen fibril formation [89], A progres sive loss of heparan sulfate proteoglycans due to a de creased synthesis and incorporation into the glomerular basement membrane has been recently found to occur in nephrotic patients with diabetic mellitus; this loss results in alteration of the charge-selective properties of the glo merular basement membrane which in turn may enhance transglomerular passage of anionic and neutral plasma proteins [95]. Therapeutic intervention with antithrom botic agents offers the potential for limiting the progres sion of renal injury.…”

“…It has been demonstrated that unfractionated heparin, in addition to inhibiting the coagulation cascade, thereby preventing excessive thrombin generation and intraglo merular fibrin deposition, may also protect the kidney through an antiproliferative effect on glomerular mesan gial cells [96] analogous to that exerted on vascular smooth muscle cells [89,97], The inhibition of cultured mesangial cell growth in vitro by heparin has been charac terized to be reversible, providing evidence for a cytostat ic activity rather than a cytotoxic one, and highly specific on the basis of a comparatively poor effect of other glycosaminoglycans [96].…”

Functional rescue of the glomerulosclerosis phenotype in Mpv17 mice by transgenesis with the human Mpv17 homologue

“…Remarkably, the Mpvl7 defect results in decreased rather than increased ros levels, which is in contrast to chemically-induced glomeruloscierosis models in rodents. There, a direct action of ros on the glomerular basement membrane has been established [17]. Thus, we assume that the evidence may suggest that the kidney disease constitutes the primary defect in the mutant mice, thus far it cannot be ruled out that it may be a manifestation of an earlier defect elsewhere in the organism.…”