Lipophagy deficiency exacerbates ectopic lipid accumulation and tubular cells injury in diabetic nephropathy

Abstract

Autophagy-mediated lipotoxicity plays a critical role in the progression of diabetic nephropathy (DN), but the precise mechanism is not fully understood. Whether lipophagy, a selective type of autophagy participates in renal ectopic lipid deposition (ELD) and lipotoxicity in the kidney of DN is unknown. Here, decreased lipophagy, increased ELD and lipotoxcity were observed in tubular cells of patients with DN, which were accompanied with reduced expression of AdipoR1 and p-AMPK. Similar results were found in db/db mice, these changes were reversed by AdipoRon, an adiponectin receptor activator that promotes autophagy. Additionally, a significantly decreased level of lipophagy was observed in HK-2 cells, a human proximal tubular cell line treated with high glucose, which was consistent with increased lipid deposition, apoptosis and fibrosis, while were partially alleviated by AdipoRon. However, these effects were abolished by pretreatment with ULK1 inhibitor SBI-0206965, autophagy inhibitor chloroquine and enhanced by AMPK activator AICAR. These data suggested by the first time that autophagy-mediated lipophagy deficiency plays a critical role in the ELD and lipid-related renal injury of DN.

Formononetin Attenuates Renal Tubular Injury and Mitochondrial Damage in Diabetic Nephropathy Partly via Regulating Sirt1/PGC-1α Pathway

“…Renal tubular damage appears to have a key role in DN, according to growing evidence ( Han et al, 2021 ; Yang et al, 2021 ; Li et al, 2022 ), and mitochondrial abnormalities largely contribute to this process ( Xiang J. et al, 2022 ; Liu et al, 2022 ). Mitochondria is in a dynamic equilibrium of fission and fusion, which is called mitochondrial dynamics, and the dynamic balance is essential for maintaining normal mitochondrial structure, number, distribution, and function ( Youle and van der Bliek, 2012 ; Chan, 2020 ).…”

Flazin as a Lipid Droplet Regulator against Lipid Disorders

“…Lipid-storage disorders, such as ELA, disrupt lipid homeostasis and cause a series of serious metabolic diseases. ELA in the tubular portion of the kidney induces lipotoxicity, which is considered a novel mechanism for the progression of DN [ 8 ]. Recent studies suggested that the management of lipid metabolism contributes to the treatment of this diabetic complication [ 30 , 31 ].…”

“…It was reported that, during DN, LDs accumulate in the tubular portion of the kidney, which is one of the main sites of DN lesions [ 7 ]. This lipid-storage disorder induces lipotoxicity by promoting inflammation, producing reactive oxygen species, and causing cell death [ 8 ]. The increasing knowledge on the association between ELA and DN has driven researchers to consider novel therapeutic strategies for DN that aim to regulate LDs, reverse lipid disorder, and maintain lipid homeostasis.…”

The critical role of dysregulated autophagy in the progression of diabetic kidney disease

“…To investigate the specific mechanism of fenofibrate on the DKD model, researchers found that fenofibrate induced autophagy and acted as an antioxidant via the AMPK pathway ( Sohn et al, 2017 ). In addition, researchers have experimentally demonstrated that the use of therapeutic agents and approaches such as mitoQ (mitochondria-targeted antioxidant) and NSC697923 inhibitor and t-AUCB (an inhibitor of soluble epoxide hydrolase) can slow down the progression of DKD by improving autophagy ( Xiao et al, 2017 ; Pontrelli et al, 2018 ; Jiang et al, 2020 ; Han et al, 2021 ; Liang et al, 2021 ; Zheng et al, 2021 ). In summary, autophagy plays an important role in maintaining the homeostasis and function of renal tubular epithelial cells.…”