Abstract
Podocyte injury and loss critically contribute to the pathogenesis of proteinuric kidney diseases including diabetic nephropathy. Deregulated lipid metabolism with disturbed free fatty acid (FFA) metabolism is a characteristic of metabolically unhealthy obesity and type 2 diabetes and likely contributes to end-stage kidney disease irrespective of the underlying kidney disease. In the current review, we summarize recent findings related to FFAs and altered renal FFA metabolism with a special focus on podocytes. We will outline the opposing effects of saturated and monounsaturated FFAs and a particular emphasis will be given to the underlying molecular mechanisms involving insulin resistance and endoplasmic reticulum homeostasis. Finally, recent data suggesting a critical role of renal FFA metabolism to adapt to an altered lipid environment will be discussed.
Highlights
Diabetic nephropathy (DN) is the major cause of end-stage renal disease, and most affected patients have type 2 diabetes [1, 2]
Several mechanisms can explain the protective effect of monounsaturated fatty acid (MUFA) in podocytes including attenuation of the palmitic acid-induced C/EBP homologous protein (CHOP) upregulation and stimulation of fatty acid β-oxidation
The potentially crucial importance of β-oxidation is supported by genome-wide association studies in type 2 diabetic patients, which found that a single-nucleotide polymorphism in ACC2 favoring impairment of β-oxidation is associated with proteinuria
Summary
Diabetic nephropathy (DN) is the major cause of end-stage renal disease, and most affected patients have type 2 diabetes [1, 2]. The epidemic of DN and type 2 diabetes parallels the obesity epidemic [7, 8], which drives other causes of chronic kidney disease (CKD) including obesity-related glomerulopathy and secondary focal segmental glomerulosclerosis [reviewed in Ref. Lipid excess and deregulated lipid metabolism in the kidney are increasingly recognized as pathogenic factors in the development and progression of obesity-related renal disease and DN but they may contribute to CKD irrespective of the underlying pathology [9]. Excessive lipid droplets can be found in different renal cell types including podocytes [9, 11]. Accumulation of lipids in non-adipose tissues can contribute to cellular dysfunction and cell death, a phenomenon that is called lipotoxicity. Recent data indicate that cholesterol accumulation in podocytes plays a critical pathogenic role in DN and contributes to lipotoxicity [12].
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