Susceptibility of Podocytes to Palmitic Acid Is Regulated by Stearoyl-CoA Desaturases 1 and 2

Abstract

Type 2 diabetes mellitus is characterized by dyslipidemia with elevated free fatty acids (FFAs). Loss of podocytes is a hallmark of diabetic nephropathy, and podocytes are highly susceptible to saturated FFAs but not to protective, monounsaturated FFAs. We report that patients with diabetic nephropathy develop alterations in glomerular gene expression of enzymes involved in fatty acid metabolism, including induction of stearoyl-CoA desaturase (SCD)-1, which converts saturated to monounsaturated FFAs. By IHC of human renal biopsy specimens, glomerular SCD-1 induction was observed in podocytes of patients with diabetic nephropathy. Functionally, the liver X receptor agonists TO901317 and GW3965, two known inducers of SCD, increased Scd-1 and Scd-2 expression in cultured podocytes and reduced palmitic acid-induced cell death. Similarly, overexpression of Scd-1 attenuated palmitic acid-induced cell death. The protective effect of TO901317 was associated with a reduction of endoplasmic reticulum stress. It was lost after gene silencing of Scd-1/-2, thereby confirming that the protective effect of TO901317 is mediated by Scd-1/-2. TO901317 also shifted palmitic acid-derived FFAs into biologically inactive triglycerides. In summary, SCD-1 up-regulation in diabetic nephropathy may be part of a protective mechanism against saturated FFA-derived toxic metabolites that drive endoplasmic reticulum stress and podocyte death.

Stearoyl-CoA Desaturase-1 Protects Cells against Lipotoxicity-Mediated Apoptosis in Proximal Tubular Cells

“…In addition to intra-renal lipolysis, this study demonstrated, for the first time, that intra-renal desaturation of SFAs by SCD1 is also a therapeutic target for the prevention of PTEC damage in diabetic nephropathy. Furthermore, a previous report has shown that SCD1 activation has a cell-protective role in glomerular epithelial cells [30]. Given that SFA-mediated cellular toxicity contributes to both tubulointerstitial lesions and podocyte injury, stimulating SCD1 activity may become a novel therapeutic target for improving the renal prognosis by both reducing proteinuria and ameliorating PTEC damage in the refractory diabetic nephropathy.…”

Lipid biology of the podocyte—new perspectives offer new opportunities

“…124 Both endoplasmic reticulum stress and podocyte cell death could be ameliorated by inducing stearoyl-CoA desaturase 1, which converts saturated FFAs to monounsaturated FFAs and is upregulated in podocytes in biopsy samples from patients with DKD (Figure 2). 125 …”

The Lentiviral System Construction for Highly Expressed Porcine Stearoyl‐CoA Desaturase‐1 and Functional Characterization in Stably Transduced Porcine Swine Kidney Cells

“…Wilson et al () concluded that the depression of SCD1 gene expression as the result and not the cause of the diabetic state. Palmitic acid‐induced podocyte death was protected by pharmacologically stimulated SCD1 expression (Sieber et al, ; Sieber and Jehle, ); podocyte death in the kidney is critical in the pathogenesis of diabetic nephropathy. The very low level of SCD1 expression in the control SK6 suggests that this porcine kidney cell line does not reflect lipid metabolism in the kidney of whole animals.…”