Free Fatty acids and their metabolism affect function and survival of podocytes

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.

Keywords: diabetic nephropathy; endoplasmic reticulum stress; lipid metabolism; lipotoxicity; podocyte; saturated and monounsaturated free fatty acids; β-oxidation.

Figure 1

(A) Tracing studies with tritium-labeled palmitic acid reveal that MUFAs such as oleic acid slightly reduce the total amount of [³H]palmitic acid containing DAG + TG in the cellular lipid fraction. In addition, oleic acid leads to a preferential incorporation of [³H]palmitic acid into TG vs. DAG. (B) Total amount of tritium-labeled metabolites recovered in the total cellular lipid fraction was decreased in the presence of oleic acid. Adapted from Sieber et al. (37). n = 9; *p < 0.01, **p < 0.00001.

Figure 2

Working model for increased plasma FFA levels and/or a shift toward SFAs on podocytes. In obesity and type 2 diabetes, increased adipose tissue lipolysis and/or a FFA uptake defect of adipocytes together with increased dietary FFA intake results in elevated plasma FFAs and a “spillover” of FFAs to non-adipose tissues including the kidney and podocytes. Podocytes may adapt to the altered lipid environment by upregulating fatty acid β-oxidation, TG synthesis, and the adaptive branch of the UPR. However, impaired adaptive capacity (e.g., genetic) or chronic “overload” leading to accumulation of toxic FFA metabolites and/or excessive TG storage may lead to diminished podocyte function and ultimately podocyte death resulting in obesity-related glomerulopathy and DN.