Type 2 diabetes is characterized by dyslipidemia with elevated free fatty acids (FFAs). Loss of podocytes is a hallmark of diabetic nephropathy, and podocytes are susceptible to saturated FFAs, which induce endoplasmic reticulum (ER) stress and podocyte death. Genome-wide association studies indicate that expression of acetyl-CoA carboxylase (ACC) 2, a key enzyme of fatty acid oxidation (FAO), is associated with proteinuria in type 2 diabetes. Here, we show that stimulation of FAO by aminoimidazole-4-carboxamide-1β-D-ribofuranoside (AICAR) or by adiponectin, activators of the low-energy sensor AMP-activated protein kinase (AMPK), protects from palmitic acid-induced podocyte death. Conversely, inhibition of carnitine palmitoyltransferase (CPT-1), the rate-limiting enzyme of FAO and downstream target of AMPK, augments palmitic acid toxicity and impedes the protective AICAR effect. Etomoxir blocked the AICAR-induced FAO measured with tritium-labeled palmitic acid. The beneficial effect of AICAR was associated with a reduction of ER stress, and it was markedly reduced in ACC-1/-2 double-silenced podocytes. In conclusion, the stimulation of FAO by modulating the AMPK-ACC-CPT-1 pathway may be part of a protective mechanism against saturated FFAs that drive podocyte death. Further studies are needed to investigate the potentially novel therapeutic implications of these findings.

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.

Sterile inflammation is considered critical in the pathogenesis of diabetic nephropathy (DN). Here we show that Fetuin‐A (FetA) or lipopolysaccharide (LPS) exacerbate palmitic acid‐induced podocyte death, which is associated with a strong induction of monocyte chemoattractant protein‐1 (MCP‐1) and keratinocyte chemoattractant (KC). Moreover, blockage of TLR4 prevents MCP‐1 and KC secretion and attenuates podocyte death induced by palmitic acid alone or combined with FetA. In addition, inhibition of interleukin‐1 (IL‐1) signaling by anakinra, a recombinant human IL‐1Ra, or a murinized anti‐IL‐1β antibody attenuates the inflammatory and ultimate cell death response elicited by FetA alone or combined with palmitic acid. In vivo short‐term therapy of diabetic DBA/2J mice with an anti‐IL1‐β antibody for 4 weeks prevented an increase in serum FetA and considerably decreased urinary tumor necrosis alpha (TNF‐α), a known risk factor for DN progression. In summary, our results suggest that FetA similarly to LPS leads to an inflammatory response in podocytes, which exacerbates palmitic acid‐induced podocyte death and our data imply a critical role for IL‐1β signaling in this process. The study offers the rational for prolonged in vivo studies aimed at testing anti‐IL‐1β therapy for prevention and treatment of DN.

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