Aspect Of Glomerular Basement Membrane Research Articles

Hyperglycemia and mechanical stress: Targeting the renal podocyte

Hyperglycemia and deriving from glomerular hypertension mechanical stress are the key factors underlying pathogenesis of diabetic nephropathy (DN). Multiple direct and secondary effects of both these factors are mediated by complex signaling pathways with extensive interactions. The common signaling pathways stimulated by high glucose and mechanical insult may act in an additive manner, thereby accelerating the cell damage. Podocytes, the cells covering the outer aspect of glomerular basement membrane (GBM), are subjected not only to the load of filtered glucose but also to diverse mechanical forces. Bulging into the Bowman's space, they have no support from the apical side, which makes them particularly susceptible to the effects of mechanical strain. Both high glucose and mechanical stress may impair the protein systems anchoring the podocyte foot processes in GBM, therefore blunting resistance of these cells to mechanical forces. Modulation by these factors of expression and activity of numerous structural and functional proteins results in the (auto)inflammatory responses, dysfunction, apoptosis or necrosis of the podocytes. Loss of the podocytes is irreversible due to their inability to proliferate and to replenish damaged cells. Podocytes are injured early in the course of DN, which, most likely, underlies further glomerular and renal damage in diabetes. This review summarizes the effects of elevated glucose and mechanical stress that seem to be involved in podocyte impairment in diabetes, with particular focus on the possible interactions between these factors.

Electron microscopic autoradiographic study on immune complex formation in rat glomerulus with anti-heparan sulfate proteoglycan antibody

Using electron microscopic autoradiography, we studied the mechanism of the formation of immune complex in the subepithelial aspect of glomerular basement membrane in rats, as a model for glomerulonephritis in man. Rats were immunized with normal rabbit IgG, and were administered intravenously with radioiodinated rabbit anti-heparan sulfate proteoglycan (HS-PG) antibody. Two weeks later the center of the grains appeared to correspond with the center of the subepithelial electron dense deposits, thus suggesting a topological superimposition of the radioiodinated anti-HS-PG antibody over the immune complex deposits located in the subepithelial space. From our present study it has become clear that the HS-PG site may serve as the corenidus for the formation of immune complex deposit. Electron microscopic autoradiography is very helpful in the demonstrating ofin situ immune complex formation in glomerulonephritis.

Basement membrane collagen in the kidney: Regional localization of novel chains related to collagen IV

Variability in the collagen chain composition of renal basement membranes was demonstrated by immunofluorescent microscopy using polyclonal and monoclonal antibodies and correlating with imaging of the glomerular basement membrane by phase microscopy. Antibodies toward the globular domains of alpha 1(IV) and alpha 2(IV) collagen chains, triple helical and 7S domains of collagen IV bind within the glomerulus to mesangial matrix, along the subendothelial region of the glomerular capillary wall, and to all tubular and vascular basement membranes. The portion of glomerular basement membrane corresponding to the phase dense image is not reactive with these antibodies. A different binding pattern is seen with antibodies against two novel globular regions of basement membrane collagen chains which bind to the phase dense aspect of glomerular basement membrane and to Bowman's capsule. Human tubular basement membrane is not reactive, except along portions of the distal tubule, whereas bovine tubular basement membrane is diffusely reactive; mesangial matrix and extraglomerular vascular basement membranes are not reactive. Although a possible explanation for the regional distribution of basement membrane collagen antigens in the glomerulus may relate to antigen exposure, a more likely reason is that collagen chains are regionally expressed. The staining patterns suggest that the novel collagen chains have a selective tissue distribution compared with alpha 1(IV) and alpha 2(IV) chains and that the glomerular cells of origin of these collagen IV chains may differ.

Mesangiolysis in diabetic glomeruli: Its role in the formation of nodular lesions

In order to elucidate a participation of the mesangiolysis in the formation of diabetic nodular lesions, 355 kidney specimens obtained from 327 patients with primary diabetes mellitus were studied. Mesangiolyses begun by focal and segmental disintegration of the pivotal structure of the mesangium ("torn off phase"), resulting in cystic or aneurysmal dilatation of the involved tuft, were found in 56 specimens (16%). The dilated tufts were filled with lysed mesangial matrix, which showed a reticular or fibrillar arrangement ("structureless phase"), being followed by a concentrical re-arrangement ("reconstructive phase") and by the ultimate formation of diabetic nodules. The mesangiolysis of various phases was frequently found concomitant with severe diabetic arteriolosclerosis and, in the reconstructive phase, the lysed mesangial matrix near the recanalized capillary along the inner aspect of glomerular basement membrane was observed to be rearranged in a layered structure. These results suggest the hypothesis that: 1) the mesangiolysis is the initial lesion occurring in glomeruli in the process of diabetic nodule formation, and disturbed blood flow into glomeruli, caused by diabetic arteriolosclerosis, may be implicated in the development of the mesangiolysis; and 2) concentric compression of the lysed mesangial matrix by recanalized capillaries forms layered structures and ultimate completed diabetic nodules.