Harnessing Calcium‐Oxalate‐ (CaOx‐) Nanocrystal‐Induced Prodeath Autophagy for Attenuating Human Renal Proximal Tubular Epithelial Cell Injury

Abstract

Calcium oxalate (CaOx) stone is the most common type of kidney stone, with a formation process comprising supersaturation, nucleation, growth, aggregation to crystals, and adhesion on renal tubular epithelial cells. CaOx stones generally lead to renal injury; however, the underlying mechanism remains poorly understood. Accumulating evidence suggests that nanosized materials could induce much greater toxicity than bulk materials with the same components. As aggregation to nanocrystals is necessary to form CaOx stones and nanocrystals have been widely reported to elicit either prodeath or prosurvival autophagy, the aim is to address the precise role of autophagy in CaOx‐ nanocrystal‐induced cytotoxicity. Clinical CaOx stones from patients are collected followed by ball milling. As a result, CaOx nanocrystals significantly reduce renal cell viability in a dose‐ and time‐dependent manner. Further study shows that CaOx nanocrystals possess an autophagy‐inducing capacity and autophagic flux is complete. Autophagy abrogation by specific chemical inhibitor wortmannin or chloroquine obviously attenuates cytotoxicity, strongly suggesting that prodeath autophagy contributes to CaOx nanocrystals‐elicited cytotoxicity. Finally, it is revealed that autophagy is an essential signaling pathway participating in apoptosis regulation. Collectively, the findings demonstrate the role of autophagy in CaOx‐nanocrystal‐elicited cytotoxicity, and harnessing autophagy can be helpful to design promising strategies for attenuating kidney injury in nephrolithiasis.

Pro-Death or Pro-Survival: Contrasting Paradigms on Nanomaterial-Induced Autophagy and Exploitations for Cancer Therapy

“…We demonstrated this phenomenon for gold NPs, as an illustrative example here (Figure a), and for many other nanomaterials such as Nd 2 O 3 NPs, ZnO NPs, Nano-C60, and MnO nanocrystals . Similar observations have been made by other laboratories for carbon dots, gold nanospikes, CeO 2 NPs, iron oxide NPs, CaOx nanocrystals, Fe@Au NPs, CoCrMo NPs, and halloysite nanotubes, etc. These nanoparticles, mostly inorganic in nature and undigestible by lysosomal enzymes, may cause disruptive effects on autophagic flux, which refers to the entire process of autophagy from autophagy initiation to autophagy termination.…”

Association between aldehyde exposure and kidney stones in adults

“…Many investigations on the mechanism of kidney stone formation have also been conducted, including the theory of renal calcium plaques, the theory of supersaturated crystallization, the theory of matrix, the theory of inhibitor shortage, and the theory of immunological damage ( 30 ). The hypothesis of supersaturation crystallization is the most researched mechanism, and its particular processes include supersaturation, crystal nucleation, aggregation, crystal development, deposition, and stone production ( 31 ). However, the specific mechanism of formation is still unknown, and these studies on the mechanism of formation of kidney stones are all at the molecular biology level, whereas there are few reports on the impact of the external environment that is closely related to human life on the formation of kidney stones, and it has not piqued people's interest.…”

Ginsenoside Rg1 and Resveratrol Alleviate Acute Kidney Injury Induced by Cisplatin via Downregulation of Autophagy in Mice

“…Jiang et al showed that autophagy had a protective effect on AKI [8]. Chen et al demonstrated the role of autophagy in CaOx-nanocrystalline-induced cytotoxicity, using autophagy to help design promising strategies to alleviate renal injury in patients with kidney stones [17]. Huang et al found that resveratrol protects podocyte cells from apoptosis by stimulating autophagy in a mouse model of diabetic nephropathy [18].…”