Effects of acute high glucose on TGF‐β1 in renal mesangial cells

Diabetic complications are a major cause of morbidity and mortality, including heart failure, blindness, and renal failure. Diabetic nephropathy (DN) is the most common cause of renal disease in the U.S. resulting in 43% of end‐stage renal disease cases. DN is characterized by changes in the renal glomerulus that are typically manifested by early signs of mesangial cell proliferation and later findings of increased ECM deposition. Many of the long‐term renal effects of diabetes are related to increased renal TGF‐βproduction. While these long‐term renal effects of hyperglycemia are well documented, its short‐term effects have not been fully considered. We have demonstrated in immortalized rat mesangial cells that 2h exposure to 25 mM glucose leads to activation of the PI3K‐Akt pathway and provided a link to its negative regulation of TGF‐β. The current study tests the hypothesis that acute high glucose exposure leads to decreased TGF‐β1 production in mesangial cells. To this end, mesangial cells were treated with 5 mM (addition of 20 mM mannitol controls for osmolarity) or 25 mM glucose for 2h. In order to assess the effect of acute high glucose, we assayed for TGF‐β1 gene expression and protein secretion by qRT‐PCR and ELISA, respectively. Our studies indicate that TGF‐β1 transcription is downregulated and that secreted TGF‐β1 levels are significantly lower in cells exposed to high glucose. Our results suggest that although long‐term exposure to high glucose leads to increased levels of TGF‐β, the initial response of mesangial cells may be to decrease TGF‐β1 production and secretion. Supported by: R21DK629086‐01 and The Kentucky Research Challenge Trust.