Vascular hypertrophy in experimental diabetes. Role of advanced glycation end products.

Abstract

The accelerated formation of advanced glycation end products (AGEs) and the overexpression of transforming growth factor beta (TGF-␤ ) have both been implicated in the pathogenesis of diabetic microvascular and macrovascular complications. Previous studies in our laboratory have demonstrated that the vascular changes in diabetes include hypertrophy of the mesenteric vasculature. To examine the role of AGEs in this process, streptozotocin-induced diabetic rats and control animals were randomized to receive aminoguanidine, an inhibitor of AGE formation, or no treatment. Animals were studied at 7 d, 3 wk, and 8 mo after induction of diabetes. When compared with control animals, diabetes was associated with an increase in mesenteric vascular weight and an increase in media wall/lumen area. By Northern analysis, TGF-␤ 1 gene expression was increased 100-150% ( P Ͻ 0.01) and ␣ 1 (IV) collagen gene expression was similarly elevated to 30-110% compared to controls ( P Ͻ 0.05). AGEs and extracellular matrix were present in abundance in diabetic but not in control vessels. Treatment of diabetic rats with aminoguanidine resulted in significant amelioration of the described pathological changes including overexpression of TGF-␤ 1 and ␣ 1 (IV) collagen. These data implicate the formation of AGEs in TGF-␤ overexpression and tissue changes which accompany the diabetic state. ( J.

Renoprotective effects of vasopeptidase inhibition in an experimental model of diabetic nephropathy

“…High dose omapatrilat not only reduced TGFβ1 expression but also decreased TGFβ1 bioactivity in a similar manner, as measured by the expression of the TGFβ1 dependent matrix protein βig-h3. This novel matrix protein has been previously shown to reflect the activity of TGFβ1 in both the human and experimental context [40,50], although the function of βig-h3 in renal physiology and pathogenic states remains unclear [22]. The lack of effect of perindopril or lowdose omapatrilat on TGFβ1 expression in these diabetic SHR, yet improvement in renal structural injury, emphasises that TGFβ1 alone cannot explain diabetes associated renal structural injury.…”

“…The site specific expression of both TGF-β and βig-h3 mRNA was assessed by in situ hybridization, and done as previously reported [40,41]. Briefly, four micron kidney sections were hybridised following digestion with PronaseE at 37°C.…”

“…The sections were then fixed in 4% paraformaldehyde and treated with a progressive haematoxylin/eosin stain. Background hybridization was controlled for by the inclusion of a sense riboprobe in a method previously described [22,40]. Quantitation of the data was done on the renal cortex and corticomedullary junction from the autoradiography film for each probe.…”

Age-dependent accumulation of advanced glycation endproducts is accelerated in combined hyperlipidemia and hyperglycemia, a process attenuated by L-arginine

“…with streptozotocin (Sz, 50mg/kg body weight) freshly solved in 50 mmol/I citrate buffer pH 4.5 (20), and (ii) hyperlipidemics (H) fed the same fat-rich diet (15). No insulin was administer to the HD group to correct hyperglycemia.…”

“…In view of the enhanced and accelerated deleterious effects of hyperglycemia when hyperlipemia was additionally present (18) we have concentrated the attention on the vascular mesenteric bed (containing the resistance arteries involved in blood pressure regulation) and on the lens (a target of diabetic complications). The mesenteric vascular bed is known to accumulate AGE-collagen during advanced chronological age (19) and in diabetes, which caused also the hypertrophy of the mesenteric vasculature (20,21). The lens crystallin glycated in vitro showed a preferential glycation of oLA crystallin subunits (6); in the diabetic (cataractous) lens crystallin accumulation of AGE-proteins was reported (22,23,24).…”