Significant glomerular basement membrane thickening in hyperglycemic and normoglycemic diabetic‐prone BB Wistar rats

Abstract

The diabetic-prone BioBreeding Wistar rat (BB/DP) is an autoimmune model of insulindependent diabetes mellitus. Approximately 80 -90% of the animals are hyperglycemic (BB/ DP h ) by 90 -120 days of age while those that do not become diabetic in adolescence (BB/DP n ) remain normoglycemic for life. Likewise, rats in the diabetes-resistant (BB/DR) strain are normoglycemic. Although renal morphological studies have been carried out in this model, ultrastructural observations of age-and diabetes-related extracellular matrix (ECM) changes, including glomerular basement membrane (GBM) morphometry, are not available. Moreover, possible renal changes in the relatively uncommon BB/DP n control animals have not been reported. The current electron microscopic study was carried out to investigate temporal changes in detergent-treated acellular ECM in BB/DP h rats at 2 weeks, 3 months, 6 months, and 1 year postonset of moderate hyperglycemia. Age-matched BB/DR and BB/DP n control animals were also examined. Our data demonstrate age-and diabetes-related alterations in mesangial matrix distributions and GBM widths and show for the first time significant increases in GBM thickening in both hyperglycemic (BB/DP h ) and normoglycemic (BB/DP n ) rats when compared to age-matched BB/DR controls. Surprisingly, the rate of increase is greatest in BB/DP n animals. Although the pathogenesis of diabetic basement membrane disease is not completely understood, GBM thickening is widely regarded as a morphological consequence of hyperglycemia. However, data in the current investigation show that ECM alterations, including significantly increased GBM thickness, may occur in genetically diabetic animals in the absence of hyperglycemia. © 2004 Wiley-Liss, Inc. Key words: diabetes; glomerular basement membrane thickness; BB Wistar ratsThe BioBreeding Wistar rat (BB rat) is an autoimmune model of insulin-dependent diabetes mellitus (IDDM) discovered in 1974 in a colony of pathogen-free Wistar rats (Chappel and Chappel, 1983). Like human IDDM, the onset of clinical symptoms in diabetes-prone (BB/DP) BB rats appear during adolescence, generally between 60 and 120 days of age (Butler et al., 1983;Chappel and Chappel, 1983). These are characterized by rapid weight loss, polyuria, polydipsia, ketonuria, and finally death unless exogenous insulin is administered (Chappel and Chappel, 1983;Like and Rossini, 1984). The incidence of diabetes through 120 days of age is 60 -90% in most colonies and averaged 86% in a viral antibody-free NIH colony in Worcester, Massachusetts (Crisa et al., 1992). The diabetes exhibited by BB rats is not attributed to a single dominant or recessive gene, but the etiology seems to include a genetic component (Chappel and Chappel, 1983).

Chip-based multimodal super-resolution microscopy for histological investigations of cryopreserved tissue sections

“…In particular, dSTORM allows the visualization of a ~100 nm gap between the podocytes and the endothelial cells (see the empty gap between the white arrowheads in Fig. 3d, f ), which is in agreement with the morphology of the glomerular basal membrane 45 . The identification of this feature, in particular, may be of critical value for a faster diagnosis of nephrotic diseases.…”

Immunohistochemical Expression Pattern of Mismatch Repair Genes in the Short-term Streptozotocin-induced Diabetic Rat Kidneys

“…1 The most typical morphologic features associated with DN are congestion and thickening of the glomerular basement membrane with consequent glomerular dysfunction and microalbuminuria, mesangial expansion, glomerular sclerosis, podocyte foot shortening, alteration of glycocalyx, etc. [2][3][4] Nevertheless, recent findings suggest that the proximal tubules might be the initial site of damage and potential therapeutic target in DN, 5 whereas some studies have pointed to the potential relevance of changes in distal tubular cells in the pathophysiology of DN. 6,7 The development of chronic diabetic complications is a compounded multistage process, which involves the modification of nitric oxide synthesis and impaired DNA repair system.…”

“…Diabetic nephropathy (DN), as a chronic complication of diabetes mellitus (DM), occurs in ~40% of diabetic patients and is the leading cause of chronic kidney disease in developed countries 1. The most typical morphologic features associated with DN are congestion and thickening of the glomerular basement membrane with consequent glomerular dysfunction and microalbuminuria, mesangial expansion, glomerular sclerosis, podocyte foot shortening, alteration of glycocalyx, etc 2–4. Nevertheless, recent findings suggest that the proximal tubules might be the initial site of damage and potential therapeutic target in DN,5 whereas some studies have pointed to the potential relevance of changes in distal tubular cells in the pathophysiology of DN 6,7.…”

Photonic chip-based multimodal super-resolution microscopy for histopathological assessment of cryopreserved tissue sections

“…A comparative view of both methods (Figure 3c) reveals structural details in d STORM that are not discernible in diffraction-limited TIRFM. In particular, d STORM allows the visualization of a ~100 nm gap between the podocytes and the endothelial cells (see the empty gap between the white arrows in Figure 3c), which is in agreement with the morphology of the glomerular basal membrane [38]. The identification of this feature, in particular, may be of critical value for a faster diagnosis of nephrotic diseases.…”