Abstract
Diabetic nephropathy is a serious complication of longstanding diabetes and its pathogenesis remains unclear. Oxidative stress may play a critical role in the pathogenesis and progression of diabetic nephropathy. Our previous studies have demonstrated that polyunsaturated fatty acids (PUFA) induce peroxynitrite generation in primary human kidney mesangial cells and heat shock protein 90β1 (hsp90β1) is indispensable for the PUFA action. Here we investigated the effects of high fat diet (HFD) on kidney function and structure of db/db mice, a widely used rodent model of type 2 diabetes. Our results indicated that HFD dramatically increased the 24 h-urine output and worsened albuminuria in db/db mice. Discontinuation of HFD reversed the exacerbated albuminuria but not the increased urine output. Prolonged HFD feeding resulted in early death of db/db mice, which was associated with oliguria and anuria. Treatment with the geldanamycin derivative, 17-(dimethylaminoehtylamino)-17-demethoxygeldanamycin (17-DMAG), an hsp90 inhibitor, preserved kidney function, and ameliorated glomerular and tubular damage by HFD. 17-DMAG also significantly extended survival of the animals and protected them from the high mortality associated with renal failure. The benefit effect of 17-DMAG on renal function and structure was associated with a decreased level of kidney nitrotyrosine and a diminished kidney mitochondrial Ca2+ efflux in HFD-fed db/db mice. These results suggest that hsp90β1 is a potential target for the treatment of nephropathy and renal failure in diabetes.
Highlights
Diabetic nephropathy is a progressive disorder in diabetic patients and worsens over time
Increased level of nitrotyrosine in proximal tubules of diabetic patients suggest that oxidative injury of the proximal tubules by peroxynitrite may play an important part in the pathogenesis and/or progression of diabetic nephropathy [5]
The deterioration in kidney functions including albuminuria and reduction of glomerular filtration rate is associated with histopathological alterations characterized by mesangial matrix expansion, glomerulosclerosis and tubulointerstitial fibrosis [27]
Summary
Diabetic nephropathy is a progressive disorder in diabetic patients and worsens over time. Hyperglycemia is known as the primary factor underlying the initiation and progression of diabetic nephropathy, the pathogenesis of diabetic nephropathy is complex and remains unclear [1]. Oxidative stress due to increased reactive oxygen species (ROS) production has been postulated to contribute to matrix accumulation, inflammation and tubulointerstitial fibrosis in the diabetic kidney [2,3,4]. Increased level of nitrotyrosine in proximal tubules of diabetic patients suggest that oxidative injury of the proximal tubules by peroxynitrite may play an important part in the pathogenesis and/or progression of diabetic nephropathy [5]. Improvement of glomerular filtration rate in type 2 diabetes patients with diminished kidney functions by bardoxolone methyl, an agonist of nuclear factor-erythroid 2-related factor 2 that regulates cytoprotective antioxidant pathways, demonstrated the efficacy of antioxidant in treating diabetic nephropathy [6,7]
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