Nephropathy in Zucker Diabetic Fat Rat Is Associated with Oxidative and Nitrosative Stress

Abstract

Abstract. Zucker diabetic fat (ZDF) rats with the metabolic syndrome and hyperlipidemia develop focal and segmental sclerosis. The role of oxidative and nitrosative stress in the nephropathy in ZDF was studied. Renal histology, function, and immunohistologic and biochemical parameters of oxidative and nitrosative stress were evaluated at 8 and 22 wk of age in ZDF and Zucker lean (ZL) rats and after chronic treatment with ebselen, an antioxidant and peroxinitrite scavenger. At 8 wk, ZDF rats showed hyperglycemia, no proteinuria or nephropathy, but higher levels of dihydrobiopterin and 3-nitrotyrosine (3-NT)-modified proteins compared with agematched ZL rats. At 22 wk, ZDF rats developed focal and segmental sclerosis, proteinuria, decreased creatinine clearance, and renal tissue levels of glutathione and tetrahydrobiopterin with further elevation in dihydrobiopterin and 3-NTmodified proteins, in contrast to age-matched ZL rats. Renal immunohistologic expression of lipid peroxidation products and 3-NT-modified proteins also increased in 22-wk-old ZDF but not in ZL rats. Chronic ebselen treatment of ZDF rats restored renal tissue levels of glutathione and tetrahydrobiopterin; prevented significant accumulation of dihydrobiopterin, lipid peroxidation products, and 3-NT-modified proteins; and ameliorated focal and segmental sclerosis, proteinuria, and fall in creatinine clearance without affecting mean BP, body weight, and blood glucose, compared with the untreated ZDF rats. Chronic ebselen therapy also ameliorated vasculopathy with lipid deposits and tubulointerstitial scarring, inflammation, and upregulated ␣-smooth muscle actin expression. These findings suggest that ZDF rats develop a progressive nephropathy with glomerular, vascular, and tubulointerstitial pathology. Oxidative and nitrosative stress predates the nephropathy, which is improved by peroxinitrite scavenger ebselen, and thus considered its cause and not consequence.The growing population of patients with the metabolic syndrome and with obesity-associated type 2 diabetes has resulted in a dramatic increase in the number of patients who have ESRD and require dialytic life support (1,2). This challenge is being met by interdisciplinary efforts to elucidate the characteristics and mechanisms of nephropathy and to develop animal models and therapeutic tools. The Zucker diabetic fat (ZDF) rat represents a well-characterized model of the metabolic syndrome. Developed more than three decades ago (3), the pathophysiologic mechanism of this model has recently been attributed to the missense mutation of leptin receptor (4). The evolution of the metabolic syndrome in the ZDF rat is associated with the development and progression of nephropathy, together with obesity, insulin resistance, hyperglycemia, and hyperlipidemia (5-10). Focal and segmental sclerosis (FSGS) develops at the age of 18 wk, although severe hyperlipidemia, hyperglycemia, and obesity predate it (8).Previous studies suggested the role of oxidative stress and endothelial dysfunction in the pathoph...

Premature vascular senescence in metabolic syndrome: Could it be prevented and reversed by a selenorganic antioxidant and peroxynitrite scavenger ebselen?

“…At 22 weeks ZDF developed FGS and increased urinary protein excretion (UPE), with amelioration of both in ZDF rats receiving ebselen. ZDF rats at 22w also had significant TIS and inflammation compared to age-matched ZL, and these manifestations of nephropathy were ameliorated with ebselen (27).…”

LR-90 prevents dyslipidaemia and diabetic nephropathy in the Zucker diabetic fatty rat

“…The ZDF rat is characterised by hyperglycaemia, hyperinsulinaemia, hyperlipidaemia, both moderate hypertension and obesity, and progressive renal injury [11,12]. These rats develop albuminuria at about 14 weeks, begin exhibiting glomerulosclerosis by 18 to 20 weeks and have increasing proteinuria resulting in chronic renal insufficiency by 22 weeks of age relative to their genetic lean controls [13][14][15]. The nephropathy in this model has been described as focal segmental glomerulosclerosis associated with glomerulomegaly and mesangial expansion [14,15].…”

“…The nephropathy in this model has been described as focal segmental glomerulosclerosis associated with glomerulomegaly and mesangial expansion [14,15]. Previous studies have shown that the development of diabetic nephropathy in obese ZDF rats can be ameliorated by treatment with peroxisome proliferator-activated receptor-gamma agonists [16,17], ACE inhibitors and angiotensin II receptor blockers (ARBs) [18,19], vasopeptidase inhibitors [19,20], antivascular endothelial growth factor antibodies [21] and antioxidants [15]. These intervention studies strongly suggest that the pathogenesis of renal damage in type 2 diabetes involves a complex interrelationship of metabolic and/or haemodynamic factors.…”

“…These rats develop albuminuria at about 14 weeks, begin exhibiting glomerulosclerosis by 18 to 20 weeks and have increasing proteinuria resulting in chronic renal insufficiency by 22 weeks of age relative to their genetic lean controls [13][14][15]. The nephropathy in this model has been described as focal segmental glomerulosclerosis associated with glomerulomegaly and mesangial expansion [14,15]. Previous studies have shown that the development of diabetic nephropathy in obese ZDF rats can be ameliorated by treatment with peroxisome proliferator-activated receptor-gamma agonists [16,17], ACE inhibitors and angiotensin II receptor blockers (ARBs) [18,19], vasopeptidase inhibitors [19,20], antivascular endothelial growth factor antibodies [21] and antioxidants [15].…”

Peroxisome proliferator-activated receptor-α activator fenofibrate prevents high-fat diet-induced renal lipotoxicity in spontaneously hypertensive rats

“…[35][36][37][38][39] In this study, we found excessive abnormal lipid accumulation in the renal tissue of SHR-HF animals compared with that in WKY-HF groups, which was related to increases in the mesangial matrix, TGF-b1 expression, apoptotic glomerular cells and the infiltration of inflammatory cells into kidneys. These findings are consistent with those of previous studies showing that lipid accumulation in kidneys promotes glomerulosclerosis through the low-density lipoprotein-receptor in mesangial cells, through macrophage chemotaxis, increased production of fibrotic cytokines and direct podocyte injury through oxidative stress.…”