Advanced oxidation protein products inhibit the autophagy of renal tubular epithelial cells

Abstract

It is well known that autophagy serves a crucial role in renal tubular epithelial cell (RTEC) injury in the pathogenesis of chronic kidney disease (CKD). The accumulation of advanced oxidation protein products (AOPPs) also participates in the progression of CKD. However, the effects of AOPPs on autophagy remain unknown. To clarify the underlying mechanism of RTEC injury in CKD, the effect of AOPPs on HK-2 cells, an RTEC cell line, was investigated. The results of the present study revealed that AOPP exposure downregulated the expression of B-cell lymphoma-2-interacting myosin-like coiled-coil protein 1, reduced the conversion of microtubule-associated proteins 1 light chain 3B (LC3)-I to LC3-II and the formation of autophagosomes, and lead to an accumulation of p62. These results suggest that AOPPs may inhibit the autophagic activity of HK-2 cells. Furthermore, the aforementioned changes were mediated by the AOPP-phosphorylated phosphoinositide 3-kinase3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway; this was verified by treatment with LY294002, a PI3K inhibitor, which reversed the AOPP-induced changes. The present study also demonstrated that the activation of autophagy with rapamycin led to an improvement in the AOPP-induced overexpression of kidney injury molecule 1 and neutrophil gelatinase-associated lipocalin, two biomarkers of RTEC injury, whereas inhibiting autophagy with chloroquine further increased their expression during AOPP treatment. Collectively, these results indicate that AOPPs may inhibit autophagy in RTECs via activation of the PI3K/AKT/mTOR pathway and that autophagy inhibition serves a role in AOPP-induced RTEC injury.

Human umbilical cord MSC‑derived hepatocyte growth factor enhances autophagy in AOPP‑treated HK‑2 cells

“…Our previous study reported that AOPP inhibited RTEC autophagy and that autophagy inhibition induced RTEC injury (5). The present study revealed that hUC-MSCs enhanced AOPP-inhibited autophagy in HK-2 cells.…”

“…Dysregulated autophagy may occur in response to either intracellular or extracellular factors, such as endoplasmic reticulum stress, oxidative stress or pathogen infection (3,4). Consistent with those findings, our previous study revealed that advanced oxidation protein products (AOPP), a toxic protein product produced in patients with CKD, induced RTEC injury by inhibiting cell autophagy (5). Therefore, enhancing RTEC autophagy may suppress the progression of CKD.…”

“…Studies have revealed that the PI3K/AKT/mTOR signaling pathway is an important negative modulator of autophagy (19,20). Our previous study revealed that AOPP inhibited HK-2 cell autophagy by activating the PI3K/AKT/mTOR signaling pathway (5).…”

Advanced Oxidation Protein Products Contribute to Renal Tubulopathy via Perturbation of Renal Fatty Acids

“…Thereafter, AOPPs are taken up by tubular cells via CD36, an AOPPs receptor. Zhang et al (34) reported that AOPPs stimulate mTOR signaling after being taken up via CD36 into HK-2 cells. This study shows that rapamycin, an mTOR inhibitor, suppresses the AOPPsinduced Elovl6 expression ( Figure 5C), suggesting that mTOR signaling contributes to Elovl6 induction by AOPPs.…”

Accelerated Kidney Aging in Diabetes Mellitus

“…In addition, the basal activity of autophagy is inhibited in intrinsic cells in diabetic kidneys [ 104 ]. The potential mechanisms might be due to the appearance of oxidative stress and inflammation secondary to stimuli such as AGEs and urinary proteins [ 105 – 107 ]. Autophagy regulates TGF- β expression and suppresses kidney fibrosis through the autophagic degradation of mature TGF- β [ 108 ], which contributes to the occurrence of diabetic diffuse glomerulosclerosis and the excessive deposition of fibrotic materials in DN [ 109 ].…”