Diabetic nephropathy and extracellular matrix

Abstract

Diabetic nephropathy (DN) is a serious complication in diabetes. Major typical morphological changes are the result of changes in the extracellular matrix (ECM). Thus, basement membranes are thickened and the glomerular mesangial matrix and the tubulointerstitial space are expanded, due to increased amounts of ECM. One important ECM component, the proteoglycans (PGs), shows a more complex pattern of changes in DN. PGs in basement membranes are decreased but increased in the mesangium and the tubulointerstitial space. The amounts and structures of heparan sulfate chains are changed, and such changes affect levels of growth factors regulating cell proliferation and ECM synthesis, with cell attachment affecting endothelial cells and podocytes. Enzymes modulating heparan sulfate structures, such as heparanase and sulfatases, are implicated in DN. Other enzyme classes also modulate ECM proteins and PGs, such as matrix metalloproteinases (MMPs) and serine proteases, such as plasminogen activator, as well as their corresponding inhibitors. The levels of these enzymes and inhibitors are changed in plasma and in the kidneys in DN. Several growth factors, signaling pathways, and hyperglycemia per se affect ECM synthesis and turnover in DN. Whether ECM components can be used as markers for early kidney changes is an important research topic, whereas at present, the clinical use remains to be established.

Figure 1.

(A) Light micrograph of a renal biopsy in diabetes illustrating glomerular changes in an otherwise nearly normal kidney. The glomerular lesion is characterized by mesangial expansion (ME) with a partly nodular pattern (N). Paraffin-embedded tissue, hematoxylin and eosin staining, original magnification ×200. (B) Light micrograph of a renal biopsy in diabetes showing glomerular, tubulointerstitial, and vascular lesions. One glomerulus shows global sclerosis (GS), the other ME. There is tubular atrophy (TA), interstitial fibrosis (IF), and focal interstitial inflammation (IFL). In an arteriole, there is substantial arteriolosclerosis (AS). Paraffin-embedded tissue, hematoxylin and eosin staining, original magnification ×200.

Figure 2.

(A) Low-power electron micrograph of a segment of a glomerulus in diabetes. The mesangial expansion (ME) shows a partly nodular pattern. The mesangial expansion appears to take place at the expense of the size of the capillary lumens (C). Epoxy-embedded tissue, original magnification ×1700. (B) Higher power electron micrograph showing thickened basement membranes (BM) typical in diabetic nephropathy. The endothelial cells (EC) and foot processes of epithelial cells (FP) are normal, whereas the mesangium (M) is expanded. Epoxy-embedded tissue, original magnification ×8000.