Abstract
Saturated fatty acid (SFA)-related lipotoxicity is a pathogenesis of diabetes-related renal proximal tubular epithelial cell (PTEC) damage, closely associated with a progressive decline in renal function. This study was designed to identify a free fatty acid (FFA) metabolism-related enzyme that can protect PTECs from SFA-related lipotoxicity. Among several enzymes involved in FFA metabolism, we identified stearoyl-CoA desaturase-1 (SCD1), whose expression level significantly decreased in the kidneys of high-fat diet (HFD)-induced diabetic mice, compared with non-diabetic mice. SCD1 is an enzyme that desaturates SFAs, converting them to monounsaturated fatty acids (MUFAs), leading to the formation of neutral lipid droplets. In culture, retrovirus-mediated overexpression of SCD1 or MUFA treatment significantly ameliorated SFA-induced apoptosis in PTECs by enhancing intracellular lipid droplet formation. In contrast, siRNA against SCD1 exacerbated the apoptosis. Both overexpression of SCD1 and MUFA treatment reduced SFA-induced apoptosis via reducing endoplasmic reticulum stress in cultured PTECs. Thus, HFD-induced decrease in renal SCD1 expression may play a pathogenic role in lipotoxicity-induced renal injury, and enhancing SCD1-mediated desaturation of SFA and subsequent formation of neutral lipid droplets may become a promising therapeutic target to reduce SFA-induced lipotoxicity. The present study provides a novel insight into lipotoxicity in the pathogenesis of diabetic nephropathy.
Highlights
In diabetic nephropathy, proteinuria is a leading cause of tubulointerstitial lesions and subsequent renal dysfunction, as well as a marker of glomerular lesions [1,2]
Among the genes associated with free fatty acid (FFA) metabolism, the mRNA expression levels of ACO, stearoyl-CoA desaturase-1 (SCD1) and ADRP were significantly decreased in the kidneys of high-fat diet (HFD)-fed obese type 2 diabetic mice (Figure 1C)
We identified SCD1, whose expression level decreased in diabetic kidneys, as a candidate FFA metabolism enzyme that can ameliorate the Saturated fatty acid (SFA)-mediated proximal tubular epithelial cell (PTEC) damage
Summary
Proteinuria is a leading cause of tubulointerstitial lesions and subsequent renal dysfunction, as well as a marker of glomerular lesions [1,2]. Growing evidence demonstrates that intra-renal lipid metabolism is altered in diabetic patients and animals, including enhanced lipogenesis and suppressed lipolysis, and that normalization of the alteration is essential for reducing FFA-mediated cytotoxicity [19,20,21,22,23] These observations led us to hypothesize that the local alteration in FFA metabolism in diabetic PTECs impairs an adaptive response against the excess inflow of urinary SFA-bound albumin. If this hypothesis is correct, revealing a unique renal lipid metabolism alteration associated with the exacerbation of SFA-mediated PTEC damage should provide a novel strategy for protecting PTECs from persistent proteinuria in diabetic nephropathy. The present study demonstrated that downregulation of stearoyl-Coenzyme A desaturase-1 (SCD1) in diabetic PTECs is associated with cell vulnerability to the cytotoxicity of SFA-bound albumin, suggesting that activation of the enzyme may become a novel therapy for protecting PTECs from refractory proteinuria in diabetic nephropathy
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
