title: Geldanamycin derivative ameliorates high fat diet-induced renal failure in diabetes.
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 Ca(2+) 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.
authors.affiliation: Department of Clinical Oncology, Xijing Hospital, The Fourth Military Medical University, Xi'an, China.
authors.forename: Hong-Mei
authors.initials: HM
authors.lastname: Zhang
authors.forename: Howard
authors.initials: H
authors.lastname: Dang
authors.forename: Amrita
authors.initials: A
authors.lastname: Kamat
authors.forename: Chih-Ko
authors.initials: CK
authors.lastname: Yeh
authors.forename: Bin-Xian
authors.initials: BX
authors.lastname: Zhang
mesh_terms: D000818:Animals; D016227:Benzoquinones / Q000008:administration & dosage*; D002118:Calcium / Q000378:metabolism; D003928:Diabetic Nephropathies / Q000150:complications* / Q000188:drug therapy* / Q000401:mortality; D059305:Diet, High-Fat / Q000009:adverse effects*; D004195:Disease Models, Animal; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors; D053208:Kaplan-Meier Estimate; D007677:Kidney Function Tests; D007678:Kidney Glomerulus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007684:Kidney Tubules / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D047029:Lactams, Macrocyclic / Q000008:administration & dosage*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D051437:Renal Insufficiency / Q000188:drug therapy* / Q000209:etiology* / Q000401:mortality; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
chemical_list: D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; C448659:17-(dimethylaminoethylamino)-17-demethoxygeldanamycin; C002744:3-nitrotyrosine; D014443:Tyrosine; D002118:Calcium