SREBP‐1 Regulates TGFβ Signaling in Kidney Mesangial Cells

Diabetic nephropathy (DN) is the most common cause of end‐stage renal disease worldwide. A key mediator in the progression of DN is the proinflammatory cytokine TGFβ. TGFβ signals through activation of Type I and II receptors (TβR1 and TβR2), followed by activation of Smads 2 and 3. Sterol regulatory element binding protein (SREBP) is a potent transcription factor known to regulate fatty acid and cholesterol biosynthesis, which has recently been implicated in the pathogenesis of DN. The aim of our study was to determine whether SREBP influenced TGFβ signaling in primary kidney mesangial cells (MC). We found that inhibition of SREBP with the small molecule inhibitor fatostatin blocked TGFβ‐induced C‐terminal phosphorylation of Smad2/3 and of Smad3 activation as assessed by SBE‐luciferase. Overexpression of dominant negative SREBP1 also attenuated Smad2/3 phosphorylation. This inhibition was not the result of an increased rate of Smad2/3 dephosphorylation, nor of Smad2/3 degradation. Rather, SREBP inhibition resulted in the loss of TβR1 protein expression without affecting its transcript levels. This appeared to be mediated by increased recruitment of Smad7 to TβRI with increased proteasomal‐mediated degradation of the receptor. Our data suggest that SREBP‐1 regulates TGFβ signaling through effects on its type I receptor. The mechanism of this regulation is being elucidated in ongoing studies.