Autophagy activation contributes to lipid accumulation in tubular epithelial cells during kidney fibrosis

Cell Death Discovery - Tập 4 Số 1
Qi Yan1, Yuan Song1, Lu Zhang1, Zhaowei Chen1, Cheng Yang1, Shan Liu2, Xinyi Yuan1, Hongyu Gao3, Guohua Ding1, Huiming Wang1
1Department of Nephrology, Renmin Hospital of Wuhan University, Wuhan, China
2Department of Nephrology, University Hospital of Hubei University for Nationalities, Enshi, China
3Department of Geriatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

Tóm tắt

AbstractSustained activation of autophagy and lipid accumulation in tubular epithelial cells (TECs) are both associated with the kidney fibrosis progression. Autophagy has been found involved in the lipid metabolism regulation through a bi-directional mechanism of inducing lipolysis as well as promoting lipid droplet formation. However, whether and how autophagy influences lipid accumulation in kidney fibrosis remain unclear. In the current study, we show that UUO-induced lipid accumulation in tubular cells was significantly reduced when the pharmacological inhibitor 3-MA or CQ was administrated both in vivo and in vitro. Of interest, colocalization of LDs and autophagosomes, as well as colocalization of LDs and lysosomes were undetected in UUO-induced fibrotic kidneys, although lysosome function remained robust, indicating the lipid accumulation is lipophagy-lysosome pathway independent. TGF-β1-induced lipid droplets formation in HK-2 cells were decreased when the Beclin-1 expression was silenced, implying that autophagy-upregulated lipid droplets formation is Beclin-1 dependent. Finally, CQ treatment of UUO-induced fibrotic kidneys reduced the expression of α-SMA and tubular cell apoptosis and rescued the expression of E-cadherin, which was associated with the ameliorated lipid deposition. Therefore, our work documented that autophagy promotes lipid droplet formation in TECs in a Beclin-1-dependent manner, which causes renal lipotoxicity and contributes to the progression of kidney fibrosis.

Từ khóa


Tài liệu tham khảo

Webster, A. C., Nagler, E. V., Morton, R. L. & Masson, P. Chronic kidney disease. Lancet 389, 1238–1252 (2017).

Choi, A. M., Ryter, S. W. & Levine, B. Autophagy in human health and disease. N. Engl. J. Med. 368, 651–662 (2013).

Cybulsky, A. V. Endoplasmic reticulum stress, the unfolded protein response and autophagy in kidney diseases. Nat. Rev. Nephrol. 13, 681–696 (2017).

De Rechter, S. et al. Autophagy in renal diseases. Pediatr. Nephrol. 31, 737–752 (2016).

Lenoir, O., Tharaux, P. L. & Huber, T. B. Autophagy in kidney disease and aging: lessons from rodent models. Kidney Int. 90, 950–964 (2016).

Tagawa, A. et al. Impaired podocyte autophagy exacerbates proteinuria in diabetic nephropathy. Diabetes 65, 755–767 (2016).

Kaushal, G. P. & Shah, S. V. Autophagy in acute kidney injury. Kidney Int. 89, 779–791 (2016).

Li, L., Zepeda-Orozco, D., Black, R. & Lin, F. Autophagy is a component of epithelial cell fate in obstructive uropathy. Am. J. Pathol. 176, 1767–1778 (2010).

Forbes, M. S., Thornhill, B. A. & Chevalier, R. L. Proximal tubular injury and rapid formation of atubular glomeruli in mice with unilateral ureteral obstruction: a new look at an old model. Am. J. Physiol. Ren. Physiol. 301, F110–F117 (2011).

Kim, W. Y. et al. The role of autophagy in unilateral ureteral obstruction rat model. Nephrology (Carlton) 17, 148–159 (2012).

Xu, Y. et al. Autophagy and apoptosis in tubular cells following unilateral ureteral obstruction are associated with mitochondrial oxidative stress. Int. J. Mol. Med. 31, 628–636 (2013).

Ding, Y. et al. Autophagy regulates TGF-beta expression and suppresses kidney fibrosis induced by unilateral ureteral obstruction. J. Am. Soc. Nephrol. 25, 2835–2846 (2014).

Kim, S. I. et al. Autophagy promotes intracellular degradation of type I collagen induced by transforming growth factor (TGF)-beta1. J. Biol. Chem. 287, 11677–11688 (2012).

Koesters, R. et al. Tubular overexpression of transforming growth factor-beta1 induces autophagy and fibrosis but not mesenchymal transition of renal epithelial cells. Am. J. Pathol. 177, 632–643 (2010).

Livingston, M. J. et al. Persistent activation of autophagy in kidney tubular cells promotes renal interstitial fibrosis during unilateral ureteral obstruction. Autophagy 23, 976–998 (2016).

Herman-Edelstein, M., Scherzer, P., Tobar, A., Levi, M. & Gafter, U. Altered renal lipid metabolism and renal lipid accumulation in human diabetic nephropathy. J. Lipid Res. 55, 561–572 (2014).

Izquierdo-Lahuerta, A., Martinez-Garcia, C. & Medina-Gomez, G. Lipotoxicity as a trigger factor of renal disease. J. Nephrol. 29, 603–610 (2016).

Xu, Y. et al. Lipid accumulation is ahead of epithelial-to-mesenchymal transition and therapeutic intervention by acetyl-CoA carboxylase 2 silence in diabetic nephropathy. Metabolism 63, 716–726 (2014).

Kang, H. M. et al. Defective fatty acid oxidation in renal tubular epithelial cells has a key role in kidney fibrosis development. Nat. Med. 21, 37–46 (2015).

Singh, R. et al. Autophagy regulates lipid metabolism. Nature 458, 1131–1135 (2009).

Shibata, M. et al. The MAP1-LC3 conjugation system is involved in lipid droplet formation. Biochem. Biophys. Res. Commun. 382, 419–423 (2009).

Liu, K. & Czaja, M. J. Regulation of lipid stores and metabolism by lipophagy. Cell Death Differ. 20, 3–11 (2013).

Lapierre, L. R. et al. Autophagy genes are required for normal lipid levels in C. elegans. Autophagy 9, 278–286 (2013).

Takagi, A. et al. Mammalian autophagy is essential for hepatic and renal ketogenesis during starvation. Sci. Rep. 6, 18944 (2016).

Susztak, K., Ciccone, E., McCue, P., Sharma, K. & Bottinger, E. P. Multiple metabolic hits converge on CD36 as novel mediator of tubular epithelial apoptosis in diabetic nephropathy. PLoS Med. 2, e45 (2005).

Decleves, A. E. et al. Regulation of lipid accumulation by AMP-activated kinase [corrected] in high fat diet-induced kidney injury. Kidney Int. 85, 611–623 (2014).

Khan, S. et al. Lipotoxic disruption of NHE1 interaction with PI(4,5)P2 expedites proximal tubule apoptosis. J. Clin. Invest. 124, 1057–1068 (2014).

Li, H. et al. Atg5-mediated autophagy deficiency in proximal tubules promotes cell cycle G2/M arrest and renal fibrosis. Autophagy 12, 1472–1486 (2016).

Rambold, A. S., Cohen, S. & Lippincott-Schwartz, J. Fatty acid trafficking in starved cells: regulation by lipid droplet lipolysis, autophagy, and mitochondrial fusion dynamics. Dev. Cell. 32, 678–692 (2015).

Levine, B., Liu, R., Dong, X. & Zhong, Q. Beclin orthologs: integrative hubs of cell signaling, membrane trafficking, and physiology. Trends Cell Biol. 25, 533–544 (2015).

Cao, Y. & Klionsky, D. J. Physiological functions of Atg6/Beclin 1: a unique autophagy-related protein. Cell Res. 17, 839–849 (2007).

Pacheco, C. D., Kunkel, R. & Lieberman, A. P. Autophagy in Niemann–Pick C disease is dependent upon Beclin-1 and responsive to lipid trafficking defects. Hum. Mol. Genet. 16, 1495–1503 (2007).

Bobulescu, I. A. Renal lipid metabolism and lipotoxicity. Curr. Opin. Nephrol. Hypertens. 19, 393–402 (2010).

Khan, S. et al. Kidney proximal tubule lipoapoptosis is regulated by fatty acid transporter-2 (FATP2). J. Am. Soc. Nephrol. 29, 81–91 (2018).

Falkevall, A. et al. Reducing VEGF-B signaling ameliorates renal lipotoxicity and protects against diabetic kidney disease. Cell. Metab. 25, 713–726 (2017).

Meyer, C., Nadkarni, V., Stumvoll, M. & Gerich, J. Human kidney free fatty acid and glucose uptake: evidence for a renal glucose-fatty acid cycle. Am. J. Physiol. 273, E650–E654 (1997).

Welte, M. A. Expanding roles for lipid droplets. Curr. Biol. 25, R470–R481 (2015).

Listenberger, L. L. et al. Triglyceride accumulation protects against fatty acid-induced lipotoxicity. Proc. Natl Acad. Sci. USA 100, 3077–3082 (2003).

Weinberg, J. M. Lipotoxicity. Kidney Int. 70, 1560–1566 (2006).

Lettieri, B. D., Tatulli, G., Aquilano, K. & Ciriolo, M. R. FoxO1 controls lysosomal acid lipase in adipocytes: implication of lipophagy during nutrient restriction and metformin treatment. Cell Death Dis. 4, e861 (2013).

Lizaso, A., Tan, K. T. & Lee, Y. H. beta-adrenergic receptor-stimulated lipolysis requires the RAB7-mediated autolysosomal lipid degradation. Autophagy 9, 1228–1243 (2013).

Ouimet, M. et al. Autophagy regulates cholesterol efflux from macrophage foam cells via lysosomal acid lipase. Cell. Metab. 13, 655–667 (2011).

Kaushik, S. & Cuervo, A. M. AMPK-dependent phosphorylation of lipid droplet protein PLIN2 triggers its degradation by CMA. Autophagy 12, 432–438 (2016).

Kaushik, S. et al. Loss of autophagy in hypothalamic POMC neurons impairs lipolysis. EMBO Rep. 13, 258–265 (2012).

Minami, S. et al. Lipophagy maintains energy homeostasis in the kidney proximal tubule during prolonged starvation. Autophagy 13, 1629–1647 (2017).

Gawriluk, T. R., Ko, C., Hong, X., Christenson, L. K. & Rucker, E. R. Beclin-1 deficiency in the murine ovary results in the reduction of progesterone production to promote preterm labor. Proc. Natl Acad. Sci. USA 111, E4194–E4203 (2014).

Ro, S. H. et al. Distinct functions of Ulk1 and Ulk2 in the regulation of lipid metabolism in adipocytes. Autophagy 9, 2103–2114 (2013).

Mehlem, A., Hagberg, C. E., Muhl, L., Eriksson, U. & Falkevall, A. Imaging of neutral lipids by oil red O for analyzing the metabolic status in health and disease. Nat. Protoc. 8, 1149–1154 (2013).

Thông tin
Thông tin xuất bản

Cell Death Discovery

Tập 4 Số 1

Thông tin tác giả