Inhibition of SREBP With Fatostatin Does Not Attenuate Early Diabetic Nephropathy in Male Mice

Abstract

Sterol regulatory element binding protein (SREBP) is an important potential mediator of kidney fibrosis and is known to be upregulated in diabetic nephropathy. We evaluated the effectiveness of SREBP inhibition as treatment of diabetic nephropathy. Type 1 diabetes was induced in uninephrectomized male CD1 mice with streptozotocin. The mice were treated with the SREBP inhibitor fatostatin for 12 weeks. At the endpoint, kidney function and pathologic findings were assessed. Fatostatin inhibited the increase of both isoforms of SREBP (types 1 and 2) in diabetic kidneys. Treatment attenuated basement membrane thickening but did not improve hyperfiltration, albuminuria, or kidney fibrosis in diabetic mice. The treatment of nondiabetic mice with fatostatin led to hyperfiltration and increased the glomerular volume to levels seen in diabetic mice. This was associated with increased renal inflammation and a trend toward increased renal fibrosis. Both in vivo and in cultured renal proximal tubular epithelial cells, fatostatin increased the expression of the proinflammatory cytokine monocyte chemoattractant protein-1. Thus, SREBP inhibition with fatostatin not only is ineffective in preventing diabetic nephropathy but also leads to kidney injury in nondiabetic mice. Further research on the efficacy of other SREBP inhibitors and the specific roles of SREBP-1 and SREBP-2 in the treatment and pathogenesis of diabetic nephropathy is needed.

Cell surface expression of 78-kDa glucose-regulated protein (GRP78) mediates diabetic nephropathy

“…Our previous studies showed that induction of type 1 diabetes in CD-1 mice with streptozotocin produces robust changes in DN (32). After 12 weeks of diabetes in this model, we assessed expression of GRP78 by IHC.…”

Advanced Oxidation Protein Products Contribute to Renal Tubulopathy via Perturbation of Renal Fatty Acids

“…diabetic nephropathy mice by producing monounsaturated FAs (40). In addition, Van Krieken et al (41) showed that inhibition of SREBP1 by fatostatin did not show a sufficient renoprotective effect in mice with diabetic nephropathy. Therefore, it is likely that Elovl6, a downstream molecule of SREBP1, rather than SREBP1 itself is a potent therapeutic target for kidney disease.…”

Use of Lipid-Modifying Agents for the Treatment of Glomerular Diseases

“…Similarly, one study demonstrated that the administration of fatostatin prevented angiotensin II-induced glomerular SREBP-1 elevation, proteinuria, and matrix accumulation in a mouse model of hypertension-induced kidney disease [ 81 ]. However, another study by the same group demonstrated that fatostatin only attenuated basement membrane thickening but failed to improve albuminuria, hyperfiltration or kidney fibrosis in a model of type 1 diabetes [ 82 ]. Additionally, SREBP inhibition with fatostatin was found to cause kidney injury in nondiabetic mice [ 82 ].…”

“…However, another study by the same group demonstrated that fatostatin only attenuated basement membrane thickening but failed to improve albuminuria, hyperfiltration or kidney fibrosis in a model of type 1 diabetes [ 82 ]. Additionally, SREBP inhibition with fatostatin was found to cause kidney injury in nondiabetic mice [ 82 ]. These divergent results may be due to the different mouse strains that were used in these studies.…”