Differential Effects of Diabetes and Glomerulonephritis on Glomerular Basement Membrane Composition

Abstract

The hallmark of renal diseases involving the glomerulus is the presence of proteinuria. While the routes of pathogenesis of proteinuria have not been established, alterations in the barrier function of the glomerular basement membrane (GBM) have been implicated. We evaluated the effect of streptozotocin diabetes and passive Heymann nephritis (PHN) over time on the macromolecular composition of rat GBM to determine if changes in composition correlate with proteinuria. Six to twelve rats from each group (control, diabetic, and PHN) were sacrificed 1, 5, 28, 56, or 84 days after induction of disease. Identical amounts of GBM were subjected to a sequential extraction procedure, and type IV collagen, entactin, laminin, fibronectin, and anionic charge content were quantitated in the extracts. Type IV collagen and entactin content did not change with time or disease. Both laminin and fibronectin contents increased with time in GBM in all groups, but this increase was significantly greater in diabetic GBM. A significant decrease in anionic charge content of GBM coincided with the onset of albuminuria at Day 28 in diabetes, but no change was seen in PHN. In diabetic rats, the increase in laminin content over control preceded the onset of albuminuria, while the increase in fibronectin was not apparent until after albuminuria was present. In PHN, no differences in type IV collagen, entactin, laminin, fibronectin, or anionic charge content of GBM were found compared with control, even though profound albuminuria was evident from Day 5 through 84. Thus, while alterations in laminin and fibronectin content may contribute to the loss of glomerular permselectivity in streptozotocin diabetes, such changes apparently are not involved in PHN.

The Use of Transgenic Animals in the Study of Diabetic Kidney Disease

“…Thus, they do not appear to be a conse− quence of defective filtration properties. This is similar to obser− vations in experimental diabetes investigating the glomerular content of laminin (total) and fibronectin [24]. During the devel− opment of the GBM, collagen type IVa1/a2, fetal laminin isotypes and fibronectin are believed to originate from endothelial cells [21,22], whereas the visceral epithelial cells are thought to be the main source of the components of the mature GBM−laminin b2 and collagen type IV a3 through a5 [21,90,91].…”

“…In diabetic nephropathy, the abnormal ECM accumulation with GBM thickening and expansion of the mesangial matrix is asso− ciated with the onset of albuminuria [24]. It has been shown that the collagen type IV (a3−a5) chains, collagen V, laminin, fibro− nectin and serum proteins contribute to thickened GBM.…”

Pathophysiology of proteinuria

“…In patients permeating the capillary wall is less marked. A loss of anionic sites of the glomerular basement membrane has with IgA nephropathy [51], whose proteinuria was less severe than that of patients with membranous nephropa-been documented in minimal change nephropathy [44,45] and in the microalbuminuric stage of diabetic nephropa-thy, the study with Ficoll confirmed that the fraction of filtrate permeating the large shunt-like pores was signifi-thy [46]. In both conditions the study with dextrans has confirmed a very mild increase of the area of the glomer-cantly increased in comparison with non-proteinuric controls.…”

Cytochemical Analysis of Pancreatic Islet Lipoapoptosis: Hyperlipidemia-Induced Cytoinvolution following Expression of the Diabetes <i>(db/db)</i> Mutation

“…Under continued dysregulated glucometabolic conditions [10,13,14], the hypercaloric nutrient intake promoted by the db/db mutation establishes a systemic hypertriglyceridemia which compromises peripheral tissue metabolic support [5,11], including the recognized disruption of normal cytoarchitecture and cellular glucose metabolism [10,13,14] by progressive hypercytolipidemia [5,11,15]. In response to chronic hypercaloric (glucose) and lipid sequestration rates, premature neuronal degeneration [16,17], hepatic lipoatrophy [10], pancreatic islet B-cell insulin degranulation and lipolipoidosis [2,11,18,19], renal cytoadiposity and glomerular filtration compromise [20,21], vascular endothelial disruption [3,15] as well as pronounced reproductive tract atrophy and sterility [3,4,[22][23][24] are recognized consequences of the chronic response to the metabolic disturbances induced by expression of the db/db mutation [5]. Ultimately, the widespread tissue involution promoted by these nonhomeostatic DOS indices results in premature pancreatic islet B-cell hyperlipidemia, islet dissolution, depressed insulin synthesis and secretion rates, as well as peripheral tissue glucometabolic dysregulation coincident with pancreatic lipoatrophy and a contracted life span in these mutants [5,11].…”