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Transcriptome analysis of isolated glomeruli from obese type 2 diabetic mice treated with enarodustat

ABSTRACT: We found that 18-week administration of a prolyl hydroxylase inhibitor, enarodustat, improved glucose/lipid metabolism of BTBR ob/ob mice, which is a model of obesity and type 2 diabetes mellitus. Enarodustat-treated mice also exhibited reduced albuminuria along with ameliorated glomerular epithelial and endothelial damage. In order to elucidate the mechanism of renoprotection, we performed microarray gene expression analysis of isolated glomeruli. The initial screening process revealed 8965 probes whose absolute values of log2 (BTBR ob/ob mice treated with enarodustat/BTBR ob/ob mice treated with vehicle-only) exceeded 0.5. We then compared the expression levels of those 8965 probes between BTBR ob/ob and wild-type mice to identify molecules that were likely to be involved in the pathogenesis of glomerular injury. Such analysis revealed 71 genes which were significantly up-regulated and 47 genes which were significantly down-regulated in BTBR ob/ob mice compared to wild-type mice. The genes were ranked according to their fold-change values, and the analysis presented Ccl2/Mcp1 as the second-most up-regulated gene in BTBR ob/ob mice. The expression level of Ccl2/Mcp1 increased by 24.42-fold in BTBR ob/ob compared to wild-type mice, and its expression in enarodustat-treated BTBR ob/ob mice was decreased to 0.62 of the vehicle-only treated BTBR ob/ob mice. Urinary CCL2/MCP-1 was indeed decreased in enarodustat-treated BTBR ob/ob mice. In vitro experiments also showed that enarodustat suppressed palmitate-induced CCL2/MCP-1 production in murine mesangial cells. Taken together, enarodustat is likely to confer renoprotection through regulating the expression of CCL2/MCP-1 in the glomerulus.

ORGANISM(S): Mus musculus

PROVIDER: GSE131266 | GEO | 2020/04/17

REPOSITORIES: GEO

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Project description:The expression of adipogenic genes is decreased in obesity and diabetes mellitus ; Samuel T. Nadler*, Jonathan P. Stoehr*, Kathryn L. Schueler*, Gene Tanimoto, Brian S. Yandell, and Alan D. Attie*,Â§ ; Departments of * Biochemistry, and Statistics and Horticulture, University of Wisconsin, Madison, WI, 53706; and Affymetrix, Inc., Santa Clara, CA 95051 ; Communicated by Neal L. First, University of Wisconsin, Madison, WI, July 13, 2000 (received for review April 3, 2000) ; Obesity is strongly correlated with type 2 diabetes mellitus, a common disorder of glucose and lipid metabolism. Although adipocytes are critical in obesity, their role in diabetes has only recently been appreciated. We conducted studies by using DNA microarrays to identify differences in gene expression in adipose tissue from lean, obese, and obese-diabetic mice. The expression level of over 11,000 transcripts was analyzed, and 214 transcripts showed significant differences between lean and obese mice. Surprisingly, the expression of genes normally associated with adipocyte differentiation were down-regulated in obesity. Not all obese individuals will become diabetic; many remain normoglycemic despite profound obesity. Understanding the transition to obesity with concomitant diabetes will provide important clues to the pathogenesis of type 2 diabetes. Therefore, we examined the levels of gene expression in adipose tissue from five groups of obese mice with varying degrees of hyperglycemia, and we identified 88 genes whose expression strongly correlated with diabetes severity. This group included many genes that are known to be involved in signal transduction and energy metabolism as well as genes not previously examined in the context of diabetes. Our data show that a decrease in expression of genes normally involved in adipogenesis is associated with obesity, and we further identify genes important for subsequent development of type 2 diabetes mellitus. Experiment Overall Design: For obesity study, lean samples include C57BL/6J lean, (C57BL/6J X BTBR) F1 and BTBR lean, obese sampples incluse C57BL/6J-ob/ob, (C57BL/6J X BTBR) F2-ob/ob and BTBR-ob/ob. All samples are subjected to Mu11K A and B arrays. Experiment Overall Design: For diabetes study, B6-ob/ob, (C57BL/6J X BTBR) F2-ob/ob low glucose, (C57BL/6J X BTBR) F2-ob/ob medium glucose, (C57BL/6J X BTBR) F2-ob/ob high glucose, and BTBR-ob/ob samples were analyzed for genes whose expression levels changes correlated with the plasma glucose levels in these mice. All samples are subjected to Mu11K A and B arrays.

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Transcriptome analysis of isolated glomeruli from obese type 2 diabetic mice treated with enarodustat

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