SREBP‐1 Mediates Angiotensin II‐induced TGFβ Upregulation in Kidney Mesangial Cells

Angiotensin II (Ang II) is a key determinant of the progression of kidney disease of diverse etiology. Mesangial cells (MC) contribute importantly to the accumulation of glomerular matrix proteins and hence glomerular sclerosis. We recently demonstrated a role for the transcription factor sterol regulatory element binding protein (SREBP‐1), best known for its regulation of lipid metabolism, in high glucose fibrotic responses in MC. Here we assessed whether it mediated Ang II profibrotic signaling. We found that Ang II induced generation of the mature transcription factor (mSREBP‐1) in a dose‐ and time‐dependent manner in primary MC. Transcriptional activation was confirmed. The chaperone SCAP and protease S1P, as well as signaling through the Ang II type 1 receptor and PI3K/Akt were required for SREBP‐1 activation. Endoplasmic reticulum (ER) stress was a central mediator of Ang II‐induced PI3K/Akt and SREBP‐1 activation. In uninephrectomized C57BL/6 mice, Ang II infusion for 1 week upregulated expression of glomerular SREBP‐1 and the ER stress chaperone GRP78. The profibrotic cytokine transforming growth factor beta (TGFβ) is a central mediator of glomerular sclerosis. Inhibition of either ER stress or SREBP‐1 in MC prevented Ang II‐induced TGFβ upregulation. SREBP‐1 is thus an important mediator of Ang II‐induced profibrotic signaling through its effects on TGFβ upregulation.