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 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.

Targeting HSP90 Ameliorates Nephropathy and Atherosclerosis Through Suppression of NF-κB and STAT Signaling Pathways in Diabetic Mice

“…Of note, DMAG treatment attenuated the structural pathologic changes in the diabetic kidney, including glomerular hyperplasia and mesangial matrix expansion, as well as tubular atrophy, interstitial fibrosis, and inflammation, hallmarks of end-stage renal failure. In line with the recently reported effect of HSP90 inhibitor on high-fat diet-induced renal failure in diabetes (20), our work adds differences in treatment dose and duration and study samples and provides mechanistic details about the renoprotective action of DMAG in diabetic mice.…”

“…Preclinical data implicate HSP90 as a promising anti-inflammatory target in rheumatoid arthritis, systemic lupus erythematosus, uveitis, liver injury, and cardiovascular disease models (12,(15)(16)(17)(18). In diabetic animals, HSP90 inhibition improved insulin sensitivity (19), high-fat diet-induced renal failure (20), and neurodegeneration (21), but the underlying mechanisms involved in these antidiabetic actions are not well defined. Hence, in this work we investigate whether targeting HSP90 delays the progression of diabetes complications in a diabetes mouse model of concomitant renal and macrovascular disease.…”

Transcriptional and Translational Modulation of myo-Inositol Oxygenase (Miox) by Fatty Acids

“…On a long term basis, tubulo-interstitial injury could be reflected by mitochondrial dysfunctions and increased expression of extracellular matrix proteins; the changes are similar to those seen in the glomerular compartment. In line with the observations that there is hyperlipidemia and high levels of non-esterified fatty acids in type 2 diabetes, Zhang et al (14) reported that a high fat diet induces glomerular as well as tubulo-interstitial damage in db/db mice, which could be alleviated by the inhibition of hsp90 accompanied with reduced levels of renal nitrotyrosine and mitochondrial Ca 2ϩ efflux. These observations suggest that various metabolic disturbances, whether related to hyperlipidemia or hyperglycemia, induce tubular damage and subsequent tubulo-interstitial injury, although this concept has been sparsely described in the literature.…”

Rhododendron groenlandicum(Labrador tea), an antidiabetic plant from the traditional pharmacopoeia of the Canadian Eastern James Bay Cree, improves renal integrity in the diet-induced obese mouse model

“…In summary, our study demonstrates that a prolonged intake of HFD, which is accompanied by disturbed glycaemic control (notably increased insulin resistance), can lead to measurable kidney damage (Boini et al 2010;Lee et al 2012;Zhang et al 2012). Treatment with R. groenlandicum, which improved insulin sensitivity in this diet-induced obesity model (Ouchfoun et al 2015), also improves parameters of kidney integrity.…”