The Effect of PPARy Ligands on the Enhancement of Insulin Sensitizing Action Via Improving Hyperglycemia

The Diabetes Control and Complications Trial and the United Kingdom Prospective Diabetes Study reported that the strict maintenance of euglycemia by intensive insulin treatment can delay the onset and slow the progression of DN in patients with type 1 and type 2 diabetes mellitus (57,58). These studies suggested that the adverse effects of hyperglycemia are the main cause for the development of long-term complications in diabetes such as kidney disease.

TZDs as PPAR-y ligands are a new class of oral antidiabetic agents that are used widely and improve insulin resistance, hyperinsulinemia, and hyperglycemia in patients with type 2 diabetes (59-62). Because amelioration of hyperglycemia can prevent the development and progression of DN, TZDs could be renoprotective in patients with type 2 diabetes and in the corresponding animal models of the disease by their insulin sensitizing ability (63). In fa/fa rats, one of type 2 diabetic models, treatment with TZDs reduced albuminuria, improved glomerular hyperfiltration, and inhibited the histological alterations of nephropathy such as mesangial expansion and glomerulosclerosis (56,64,65). In MCs cultured in high-glucose conditions, troglitazone and 15dPGJ2 suppress the expression of a-smooth muscle actin, i.e., preventing the de-differentiation of MCs from a quiescent phenotype to a proliferative myofibroblast-like phenotype (52). Furthermore, TZDs inhibited proliferation of MCs in a dose-dependent manner (52). Taken together, these observations indicate that PPAR-y activators significantly lower blood glucose concentration and protect the kidney against hyperglycemic damage in type 2 diabetic patients and animal models.

Via Lowering Blood Pressure With or Without Improvement of Insulin Resistance

Blood pressure control is important in the treatment of chronic kidney diseases including DN (66). Hypertension is commonly linked to obesity and insulin resistance (67). This syndrome, in which insulin resistance, hypertension, obesity, dyslipidemia, and microalbuminuria are associated has been termed "the metabolic syndrome" (68,69). TZDs have the ability to lower blood pressure as well as to enhance of insulin sensitivity both in type 2 diabetic patients and animal models (70-74). Therefore, TZDs could also be effective agents in the treatment of the metabolic syndrome (75). It has been suggested that the antihypertensive effect of TZDs is a result of improved insulin resistance because insulin sensitivity has been found to be related to blood pressure levels both in diabetic animals and humans (56,71-74). On the other hand, PPAR-y ligands may also have direct effects on vascular function because PPAR-y is expressed in endothelial cells and vascular smooth muscle cells (VSMCs) (76-78). Indeed, pioglita-zone lowers blood pressure in 5/6 nephrectomized hypertensive rats, without an associated change in insulin resistance (79,80) The antihypertensive effects of TZDs could involve release of vasodilators such as nitric oxide and prostaglandins (81), decrease in FAs levels, and alterations in vasoactive peptides synthesis such as endothelin-1 (82). Recently PPAR-y was shown to downregulate the expression of angiotensin II type-1 receptor and decrease VSMC tone, thereby reducing vascular contractility (83).

In contrast, it has been suggested that PPAR-y could contribute to water and sodium retention as this isoform is predominantly expressed in collecting ducts (48). In clinical practice, caution must be paid when TZD agents are prescribed in patients with edema or congestive heart failure. Although the precise mechanisms still remain unclear, PPAR-y expression participates in blood pressure regulation via multiple mechanisms.

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