Sterol regulatory element binding protein (SREBP) is an important potential mediator of kidney fibrosis, and is known to be upregulated in diabetic nephropathy. Here we evaluate the effectiveness of SREBP inhibition as treatment for diabetic nephropathy.Type 1 diabetes was induced in uninephrectomized male CD1 mice with streptozotocin. Mice were treated with the SREBP inhibitor fatostatin for 12 weeks. At endpoint, kidney function and pathology were assessed. Fatostatin inhibited the increase of both isoforms of SREBP (1 and 2) in diabetic kidneys. Treatment attenuated basement membrane thickening, but did not improve hyperfiltration, albuminuria or kidney fibrosis in diabetic mice. Surprisingly, treatment of non-diabetic mice with fatostatin led to hyperfiltration and increased glomerular volume to levels seen in diabetic mice. This was associated with increased renal inflammation and a trend to increased renal fibrosis. Both in vivo and in cultured renal proximal tubular epithelial cells, fatostatin increased expression of the pro-inflammatory cytokine monocyte chemoattracant protein-1 (MCP-1).Thus, SREBP inhibition with fatostatin is not only ineffective in preventing diabetic nephropathy, but it also leads to kidney injury in non-diabetic mice. Further research on the efficacy of other SREBP inhibitors, and the specific roles of SREBP-1 and -2, in the treatment and pathogenesis of diabetic nephropathy need to be evaluated.
Pubmed ID: 29420703 RIS Download
Publication data is provided by the National Library of Medicine ® and PubMed ®. Data is retrieved from PubMed ® on a weekly schedule. For terms and conditions see the National Library of Medicine Terms and Conditions.