Ciglitazone, a PPARγ agonist, ameliorates diabetic nephropathy in part through homocysteine clearance

Abstract

Sen U, Rodriguez WE, Tyagi N, Kumar M, Kundu S, Tyagi SC. Ciglitazone, a PPAR␥ agonist, ameliorates diabetic nephropathy in part through homocysteine clearance. Am J Physiol Endocrinol Metab 295: E1205-E1212, 2008. First published September 9, 2008 doi:10.1152/ajpendo.90534.2008.-Diabetes and hyperhomocysteinemia (HHcy) are two independent risk factors for glomeruloslerosis and renal insufficiency. Although PPAR␥ agonists such as ciglitazone (CZ) are known to modulate diabetic nephropathy, the role of CZ in diabetes-associated HHcy and renopathy is incompletely defined. We tested the hypothesis that induction of PPAR␥ by CZ decreases tissue Hcy level; this provides a protective role against diabetic nephropathy. C57BL/6J mice were administered alloxan to create diabetes. Mice were grouped to 0, 1, 10, 12, and 16 wk of treatment; only 12-and 16-wk animals received CZ in drinking water after a 10-wk alloxan treatment. In diabetes, PPAR␥ cDNA, mRNA, and protein expression were repressed, whereas an increase in plasma and glomerular Hcy levels was observed. CZ normalized PPAR␥ mRNA and protein expression and glomerular level of Hcy, whereas plasma level of Hcy remained unchanged. GFR was dramatically increased at 1-wk diabetic induction, followed by hypofiltration at 10 wk, and was normalized by CZ treatment. This result corroborated with glomerular and preglomerular arteriole histology. A steady-state increase of RVR in diabetic mice became normal with CZ treatment. CZ ameliorated decrease bioavailability of NO in the diabetic animal. Glomerular MMP-2 and MMP-9 activities as well as TIMP-1 expression were increased robustly in diabetic mice and normalized with CZ treatment. Interestingly, TIMP-4 expression was opposite to that of TIMP-1 in diabetic and CZ-treated groups. These results suggested that diabetic nephropathy exacerbated glomerular tissue level of Hcy, and this caused further deterioration of glomerulus. CZ, however, protected diabetic nephropathy in part by activating PPAR␥ and clearing glomerular tissue Hcy.peroxisome proliferator-activated receptor-␥; matrix metalloproteinase; tissue inhibitor of metalloproteinases; glomerulosclerosis PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR-␥ (PPAR␥) is a member of nuclear hormone receptor superfamily of ligandactivated transcription factors. It plays important roles in maintaining glucose and lipid homeostasis (39). The PPAR␥ agonists, such as ciglitazone (CZ), are agents that improve glycemic control by increasing insulin sensitivity (5). These agonists also mediate direct antiatherogenic effects in the diabetic vasculature that are independent of their metabolic actions (4). In the pathogenesis of diabetic vasculopathies, such as in glomerulosclerosis, downregulated PPAR␥ expression is associated with matrix accumulation and glomerulonephritis (23,30,39). Several studies have shown the efficacy of PPAR␥ agonists to ameliorate the progression of glomerulosclerosis (15) and have suggested that PPAR␥ ligands have a direct beneficial renal effect. However, the role...

Matrix metalloproteinases in kidney homeostasis and diseases

“…These contradictions could be caused by differences in animal strains, samples obtained, and cell types examined, as well as the fact that diabetes treatment affects MMP expression (126). Some models show that decreased MMP activity, particularly of MMP-2 and MMP-9, ameliorate kidney lesions (107,114,144,150), whereas in other models maintenance of MMPs, namely, MMP-1 and in some cases even MMP-9, is associated with improvement (see Table 2) (4,34). Similarly contradictory, TIMP-3 was elevated in diabetes, but TIMP-3 null mice actually had worsened fibrosis and increased activation of MMP-2 (55,57).…”

Hydrogen sulfide ameliorates hyperhomocysteinemia-associated chronic renal failure

“…In disease condition, such as in diabetic nephropathy, Hcy disposal and clearance are impaired and therefore accumulate in the body, resulting in increase of plasma and tissue levels of Hcy (43). This, in turn, causes renal microvascular impairment and vasoconstriction (37), which lead to renal volume retention and further accumulation of Hcy (38). This is a vicious cycle and is often associated with chronic renal failure.…”

“…Previously, we have reported that reduction in renal function leads to an increased plasma Hcy level (36,38). The elevated plasma Hcy, in turn, causes renal insufficiency, which leads to a vicious cycle (22).…”

“…The elevated plasma Hcy, in turn, causes renal insufficiency, which leads to a vicious cycle (22). Accumulated evidences from independent laboratories, including our own, suggested that, at an elevated level, Hcy is an independent and graded risk factor for cardiorenovascular diseases (7,27,38). Reports are also available that it may contribute to the pathogenesis of atherosclerosis (2,26), including glomerulosclerosis, cellular apoptosis, podocyte injury, and proteinuria (22,56).…”

Cystathionine β-synthase and cystathionine γ-lyase double gene transfer ameliorate homocysteine-mediated mesangial inflammation through hydrogen sulfide generation

“…This seemingly paradoxical effect has been demonstrated with other hormones and growth factors, such as insulin (11), which decreases plasma levels of amino acids by increasing tissue uptake. Previously, we demonstrated elevated tissue levels of Hcy in the kidney (37) and heart tissue (33) of hyperhomocysteinemic mice with alloxan-induced diabetes mellitus. We also demonstrated that the level of cystathione ␥-lyase (CSE), an enzyme responsible for conversion of Hcy to H 2 S, a potent antioxidant, vasorelaxant, and antihypertensive agent, was decreased in the kidney of another model of HHcy, the uninephrectomized cystathionine ␤-synthase heterozygous (CBSϩ/Ϫ) mice (36).…”