Altered Steady-State mRNA Levels of Basement Membrane Proteins in Diabetic Mouse Kidneys and Thromboxane Synthase Inhibition

Abstract

We examined steady-state levels of mRNA encoding type IV collagen, B1 chain of laminin, and the basement membrane heparan sulfate proteoglycan in the kidney cortex of a mouse model (KKAy) of non-insulin-dependent diabetes. mRNAs encoding laminin B1 and the proteoglycan were unchanged in kidneys taken from diabetic mice with demonstrable basement membrane thickening. mRNA levels for type IV collagen, in contrast, were significantly elevated (2-fold) in diabetic mice concurrent with but not preceding morphologically thickened basement membranes. There was a negative correlation between a ratio of proteoglycan/type IV collagen and levels of albuminuria in the diabetic mice. No correlation was noted with laminin. We also examined the effects of inhibiting the synthesis of thromboxane, a potent vasoconstrictor, on the steady-state levels of type IV collagen in the diabetic mice. Inhibition of thromboxane stopped the progression of albuminuria and prevented an increase in type IV collagen mRNA levels. We conclude that basement membrane thickening in diabetes, a hallmark of diabetic nephropathy, is partly a consequence of an unbalanced increase in the production of type IV collagen. The relative decrease in proteoglycan production may contribute to chronic albuminuria.

Prevention of diabetic nephropathy in db/db mice with glycated albumin antagonists. A novel treatment strategy.

“…cortical collagen IV mRNA at age 16 wk. Increased kidney type IV collagen mRNA has been found in other rodent models of genetic and acquired diabetes (36)(37)(38). Denistometric scanning of the exposed autoradiographs allowed calculation of type IV collagen mRNA levels in relation to 18S rRNA levels.…”

Improvement of blood glucose control in IDDM patients retards the progression of morphological changes in early diabetic nephropathy

“…In the BM collagen IV, laminin and heparansulphate proteoglycan predominate while the mesangial matrix also contains collagen V, fibronectin, trombospondin, and chondroitin/dermatan sulphate proteoglycans [21]. Short-term experimental studies show that hyperglycaemia induces increased production of the aforementioned proteins, the main constituents of the extracellular material [22][23][24][25][26]. Furthermore, hyperglycaemia leads to accumulation of advanced glycated end-products of proteins.…”

Stimulation of collagen gene expression and protein synthesis in murine mesangial cells by high glucose is mediated by autocrine activation of transforming growth factor-beta.

“…In experimental animal models of diabetic renal involvement, evidence has been accumulating that increased synthesis of several extracellular matrix components is a relatively early feature ofthe disease (reviewed in references 4,8,9). Increased steady-state mRNA levels encoding collagen, laminin, and fibronectin have been described in renal cortical specimens (10)(11)(12)(13) and, more recently, in isolated whole glomeruli ( 14). It has been proposed that many abnormalities ofthe diabetic milieu may contribute to glomerulosclerosis; these include adaptive changes in glomerular hemodynamics with an increase in transcapillary hydraulic pressure, increased nonenzymatic glycosylation products, activation of the polyol pathway, and alterations in hormonal balance and other biochemical abnormalities ( 1,4,8,9,15,16).…”