Apoptosis in Glomerular Endothelial Cells during the Development of Glomerulosclerosis in the Remnant-Kidney Model

Abstract

Capillary obsolescence with subsequent glomerulosclerosis is a common finding in most progressive glomerular diseases. In this study we investigated apoptosis, focusing on glomerular endothelial cells during the development of glomerulosclerosis in five-sixths nephrectomized rats for 6 months. Apoptosis was recognized by light and electron microscopy. Biochemical labeling of apoptosis was morphologically confirmed by in situ end labeling of fragmented DNA using terminal deoxynucleotidyltransferase. Glomerular endothelial cells were identified by electron microscope and immunostaining for thrombomodulin which is known to be an endothelial cell surface glycoprotein. Glomerular hypercellularity occurred by month 2, peaking by month 3, and an extracellular matrix accumulation was evident by month 3. Subsequently, most of the glomeruli progressed to diffuse sclerosis by months 4–6. During the progression of the disease, the glomerular endothelial cells decreased in number and finally could not be detected in the sclerotic lesion, and apoptotic cells apparently increased in number in the lesion. Significant apoptosis was present from month 3, thereafter it gradually increased to peak by month 6. Double immunostaining for apoptosis and thrombomodulin demonstrated that apoptosis occurred in the glomerular endothelial cells as well as in mesangial cells and infiltrating cells. The number of glomerular endothelial cells with apoptosis increased with the development of glomerulosclerosis, and maximum expression was observed by month 6. We conclude that the depletion of glomerular endothelial cells is associated with apoptosis in the remnant-kidney model, and apoptosis in glomerular endothelial cells may contribute to the development of glomerulosclerosis.

Reversal of Glomerular Lesions Involves Coordinated Restructuring of Glomerular Microvasculature

“…Previous authors emphasized the similarities and potentially analogous mechanistic pathways when microvascular repair and glomerular development are compared (8,27). An early proliferative response of glomerular endothelial cells during the development of glomerular lesions has also been documented (28). This is not sustained, however, and in the long run, even loss of glomerular endothelial cells is observed (28,29).…”

“…An early proliferative response of glomerular endothelial cells during the development of glomerular lesions has also been documented (28). This is not sustained, however, and in the long run, even loss of glomerular endothelial cells is observed (28,29).…”

A Biomarker for Detecting Early Tubulointerstitial Disease and Ischemia in Glomerulonephropathy

“…[8][9][10][11] It has previously been noted that the reduction in peritubular capillary flow correlates inversely with the magnitude of tubulointerstitial fibrosis, and such a reduction in peritubular capillary flow precedes the development of tubulointerstitial fibrosis, thereby signifying the cause-and-effect relationship. [6] In fact, injury to the glomerular endothelium or to the peritubular capillary endothelium as reflected by an increased incidence of apoptosis, [12,13] an increased endothelial cell cytotoxicity, [7] and a defective staining of endothelial factor VIII [14] have been delineated in severe kidney diseases associated with tubulointerstitial fibrosis. A diminished vascular endothelial growth factor, which is essential to the survival of renal microvascular endothelium, correlates with the microvascular injury in chronic kidney diseases.…”

TGF-ß Signaling in Renal Disease

“…Loss of glomerular capillaries is associated with increased apoptosis of glomerular endothelial cells and correlates with the development of glomerulosclerosis in rodent models of progressive anti-GBM disease, in remnant kidney models, and in aging kidney (28,55,56). Similarly, endothelial cell (EC) apoptosis may underlie the loss of peritubular capillaries characteristically associated with tubulointerstitial fibrosis and tubular atrophy (57).…”