Molecular mechanism of renal lipid accumulation in diabetic kidney disease

Abstract

Diabetic kidney disease (DKD) is a leading cause of end stage renal disease with unmet clinical demands for treatment. Lipids are essential for cell survival; however, renal cells have limited capability to metabolize overloaded lipids. Dyslipidaemia is common in DKD patients and renal ectopic lipid accumulation is associated with disease progression. Unveiling the molecular mechanism involved in renal lipid regulation is crucial for exploring potential therapeutic targets. In this review, we focused on the mechanism underlying cholesterol, oxysterol and fatty acid metabolism disorder in the context of DKD. Specific regulators of lipid accumulation in different kidney compartment and TREM2 macrophages, a lipid-related macrophages in DKD, were discussed. The role of sodium-glucose transporter 2 inhibitors in improving renal lipid accumulation was summarized.

Keywords: SGLT2 inhibitor; cholesterol; diabetic kidney disease; fatty acid; lipid metabolism; oxysterol.

FIGURE 1

7‐ketocholesterol, 7β‐hydroxycholesterol and 25‐hydroxycholesterol are oxysterols that increased in diabetic kidneys. These oxysterols are known to have multiple effects on cellular function and survival. Further studies are needed to elucidate their role in diabetic kidney disease.

FIGURE 2

(A) Cholesterol in kidney resident cells is mainly regulated by cholesterol efflux regulatory gene ABCA1, cholesterol influx regulatory gene GPR43, cholesterol esterification regulatory gene SOAT and cholesterol synthesis rate‐limiting enzyme HMG‐CoA. Animal and in vitro studies have demonstrated that under diabetic conditions, the expression of ABCA1 is downregulated due to reduced LXR expression in GEC; in podocytes, reduction of ABCA1 leads to cardiolipin accumulation at mitochondrial, and SOAT expression correlates with intracellular cholesterol ester accumulation; in tubular cells, increase in SREBP results in elevated HMG‐CoA expression, thus accelerating cholesterol synthesis while PACS‐2 and DsbA‐L inhibits SREBP and HMG‐CoA, respectively. (B) In diabetic kidneys, cellular fatty acid uptake increases due to elevated expression of FAT and FATP. Besides, upregulated SREBP expression enhances fatty acid synthesis via FAS. In podocytes, the binding of free fatty acid and FFAR1/2/3 activates Gβ/Gγ complex and RAC1, triggers podocyte micropinocytosis; in tubular cells, free fatty acid overload generates mitochondrial dysfunction and ROS elevation. ABCA1, adenosine triphosphate‐binding cassette transporter A1; DsbA‐L, disulfide‐bond A oxidoreductase‐like protein; FAT, fatty acid translocase; FAS, fatty acid synthase; FATP, fatty acid transport proteins; FFAR, free fatty acid receptors; GEC, glomerular endothelial cell; GPR43, G‐protein‐coupled receptor 4; HMG‐CoA, β‐hydroxy β‐methylglutaryl‐CoA; LXR, liver X receptor; PACS‐2, phosphofurin acidic cluster sorting protein 2; ROS, reactive oxygen species; SOAT, sterol‐O‐acyltransferase; SREBP, sterol regulatory element‐binding protein.