Ts in Organ Specific Microvascular Alterations in Diabetes

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Diabetic Retinopathy

Diabetic retinopathy (DR) predominantly affects the vascular components of the retina. Early in the disease course, diabetes causes functional alterations such as reduced retinal blood flow [2]. With sustained hyperglycemia structural changes such as capillary BM thickening, loss of pericytes, and breakdown of intracellular endothelial cell junctions occur.

Retinal tissue is a rich source of ET-1 and ET-3 [1]. We and others have shown increased mRNA and protein expression of both ET-1 and ET-3 in retinas of diabetic animals in association with retinal vasoconstriction [1]. Blockade of ET receptor mediated signaling and ECE1, enzyme involved in ET peptide processing, prevents retinal vasoconstriction and associated structural changes.

With respect to structural changes, we have demonstrated that ET receptor blockade with dual ETA and ETB antagonist, bosentan, prevents diabetes-induced upregulation of FN and collagen alpha-1 (IV) mRNA, and increased capillary BM thickening in animals [1]. ETs could also arbitrate later stages of DR as selective ETB receptor antagonists can prevent endothelial cell proliferation and migration, two fundamental steps in the process of angiogenesis. In a few recent studies, vitreous ET-1 levels were found to be significantly elevated in patients with proliferative DR as compared to nondiabetic subjects [10].

Diabetic Nephropathy

Diabetic nephropathy (DN) remains the most common cause of renal failure. Sustained hyperglycemia leads to glomerular hyperfiltration and microalbuminuria. With progression, patients develop overt macroalbuminuria and reduced glomerular filtration rate. Pathological features of DN include mesangial matrix expansion, thickening of glomerular capillary BM and tubulointerstitial fibrosis.

ETs may regulate renal blood flow and glomerular filtration. Recent studies from our laboratory have demonstrated increased expression of ET-1, ET-3, ETA, and ETB in the diabetic rat [1]. Increased ET-1 mRNA and increased renal ET-1 clearance in association with proteinuria has been demonstrated in human diabetes. Furthermore, treatment of diabetic animals with ET receptor antagonist has been shown to prevent microalbuminuria.

Studies in rat mesangial cells have implicated ETs in regulating ECM protein production. Diabetes-induced increased expression of ECM proteins and other fibrogenic growth factors has been shown to be completely blocked by treatment with an ETA receptor antagonist and dual ETA and ETB receptor antagonist.

Diabetic Cardiomyopathy

Diabetic cardiomyopathy is a prominent cardiac complication that involves structural and functional changes in both cardiomyocytes and capillary endothelial cells. Pathological features of diabetic cardiomyopathy include myocyte hypertrophy and/or necrosis, interstitial and perivascular fibrosis, and capillary BM thickening.

ETs have been shown to be produced by both cardiomy-ocytes and endothelial cells. We have previously demonstrated upregulation of ET-1 along with ETA and ETB receptor expression in heart tissues of diabetic rats. Such alterations were associated with focal apoptosis of car-diomyocytes, scarring of the myocardium, and increased expression of ECM proteins. Inhibition of ET receptor signaling completely prevented these structural abnormalities. Furthermore, a duration-dependant alteration of chronotropic and inotropic responses to ET-1 has been demonstrated in isolated atria of diabetic rats. Recently, we have demonstrated that ET-1 may interact with sodium-hydrogen exchanger-1 (NHE-1) in mediating diabetes-induced structural and functional changes. NHE-1 may act as the downstream mediator in the development of ET-mediated functional and structural changes in diabetic myocardium.

Diabetic Neuropathy

Diabetic neuropathy is one of the most prevalent complications of chronic diabetes. The pathogenesis of diabetic neuropathy involves chronic hyperglycemic insult to both neurovasculature and neuronal parenchyma. Studies in STZ-induced diabetic rats have established a role of ETs in impairment of endoneurial blood flow. In addition, reduced NO production in the vasculature of the peripheral nerve has been demonstrated, which may further augment ET expression. ET receptor antagonism has been shown to prevent impairment of endoneurial blood flow in diabetic animals.

Neuronal parenchymal damage is believed to be due to impaired nerve conduction velocity. Impaired nerve conduction velocity has been associated PKC activity and could possibly be mediated via ETs. We have demonstrated increased immunoreactivity of ET-1 and ET-3 in peripheral nerves in diabetes. Furthermore, inhibition of ET receptor-mediated signaling has been shown to prevent early nerve conduction velocity deficits in STZ-induced diabetic rats.

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