Crosstalk Between Lipids and Mitochondria in Diabetic Kidney Disease

Abstract

Purpose of review: The goal of this review is to review the role that renal parenchymal lipid accumulation plays in contributing to diabetic kidney disease (DKD), specifically contributing to the mitochondrial dysfunction observed in glomerular renal cells in the context of DKD development and progression.

Recent findings: Mitochondrial dysfunction has been observed in experimental and clinical DKD. Recently, Ayanga et al. demonstrate that podocyte-specific deletion of a protein involved in mitochondrial dynamics protects from DKD progression. Furthermore, our group has recently shown that ATP-binding cassette A1 (a protein involved in cholesterol and phospholipid efflux) is significantly reduced in clinical and experimental DKD and that genetic or pharmacological induction of ABCA1 is sufficient to protect from DKD. ABCA1 deficiency in podocytes leads to mitochondrial dysfunction observed with alterations of mitochondrial lipids, in particular, cardiolipin (a mitochondrial-specific phospholipid). However, through pharmacological reduction of cardiolipin peroxidation DKD progression is reverted. Lipid metabolism is significantly altered in the diabetic kidney and renders cellular components, such as the podocyte, susceptible to injury leading to worsened DKD progression. Dysfunction of the lipid metabolism pathway can also lead to mitochondrial dysfunction and mitochondrial lipid alteration. Future research aimed at targeting mitochondrial lipids content and function could prove to be beneficial for the treatment of DKD.

Keywords: ABCA1; Cardiolipin; Diabetic kidney disease; Lipid metabolism; Mitochondria; Podocyte.

Figure 1.. Role of mitochondria in podocyte injury associated with DKD.

Decreased expression of ATP-binding cassette transporter 1 (ABCA1) leads to increased cholesterol and cardiolipin accumulation and alteration in OXPHOS complex, however, in a hyperglycemic state, superoxide dismutase 2 (SOD2) is reduced and together this contributes to elevated reactive oxygen species (ROS) production and oxidized cardiolipin (ox-CL). Alteration of free fatty acids (FFA) uptake through platelet glycoprotein 4 (CD36) causes triglyceride (TG)-enriched lipid droplets accumulation and increases ROS production. Hyperglycemia and increased production of advanced glycosylation end products (AGEs) lead to ROS production and podocyte injury in DKD.