Mesangial Expansion as a Central Mechanism for Loss of Kidney Function in Diabetic Patients

Abstract

Diabetic nephropathy leading to kidney failure is a major complication of both type I (insulin-dependent) and type II (non-insulin-dependent) diabetes mellitus, and glomerular structural lesions (especially expansion of the mesangium) may constitute the principal cause of decline in kidney function experienced by a significant fraction of diabetic patients. Although the biochemical bases of these mesangial abnormalities remain unknown, an understanding of the natural history of diabetic nephropathy from a combined structural and functional approach can lead to greater pathophysiological insight. Work in animals has supported the concept that the metabolic disturbances of diabetes mellitus cause diabetic nephropathy, with structural and functional lesions prevented or reversed with improved or normalized glycemic control. Additional research must address this fundamental issue in humans, especially the response of advancing mesangial lesions to improved glycemic control. Factors not directly related to the metabolic perturbations of diabetes may serve to accelerate or diminish the pathophysiological processes of diabetic nephropathy. The elucidation and management of these factors, when coupled with improved glycemic control, may moderate the development or progression of diabetic kidney lesions in humans.

Inhibiting Albumin Glycation Ameliorates Diabetic Nephropathy in the <i>db/db</i> Mouse

“…Values obtained with this method are consistent with those reported by other investigators using light- and/or electron-microscopic methods [8]. Increased mesangial fractional volume is a better indicator of declining filtration function than is width of the glomerular basement membrane [30, 31, 32]. …”

“…In its earliest phases, the development of diabetic nephropathy in human patients is heralded by increased urine albumin excretion and is manifest pathologically by an accumulation of extracellular matrix in the glomerular mesangium [31, 32, 41, 42, 43, 44, 45, 46]. The magnitude of the mesangial expansion correlates positively with both increased albumin excretion and a reduction in the glomerular filtration rate in patients with diabetic nephropathy, and there is a close inverse correlation between the degree of matrix accumulation and the glomerular surface area available for filtration [47, 48].…”

Metalloproteinases in the Pathogenesis of Diabetic Nephropathy

“…The pathological hallmarks of diabetic nephropathy are increased thickness of the glomerular basement membrane (GBM) and mesangial expansion [16, 17, 18, 19, 20]. The latter is considered more significant than thickening of the GBM as expansion of the mesangium has been reported to ultimately lead to renal insufficiency [19].…”

“…The latter is considered more significant than thickening of the GBM as expansion of the mesangium has been reported to ultimately lead to renal insufficiency [19]. These changes in the GBM and mesangium are characterized by expansion of all intrinsic components of extracellular glycoproteins, such as collagen types IV, V and VI, laminin, and fibronectin, as well as other intrinsic components of the normal renal extracellular matrix (ECM) that have not yet been identified [21, 22, 23, 24, 25, 26, 27].…”

Renal in situ Hybridization Studies of Extracellular Matrix Related Molecules in Type 1 Diabetes mellitus

“…The histological hallmarks of diabetic nephropathy (DN) included thickening of the glomerular basement membrane (GBM) and mesangial expansion [1, 2, 3], are primary due to accumulation of extracellular matrix (ECM) [1]. Mesangial expansion has been hypothesized to be the critical lesion of DN [1, 2, 3].…”