Autophagy in Kidney Health and Disease

Wang, Zhen; Choi, Mary E.

doi:10.1089/ars.2013.5363

Cited by 88 publications

(89 citation statements)

References 106 publications

(180 reference statements)

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“…It has been reported that reabsorption of albuminuria elicits autophagy in the proximal tubular epithelium as a renoprotective process, and proteinuria-induced autophagy was suppressed via hyper-activation of mTORC1 under hyperglycaemic conditions. Previous studies have showed that rapamycin treatment can ameliorate renal hypotrophy in a mouse model of diabetes via inhibition of mTORC1 [11,15,[23][24][25]. In addition, mTOR signaling inhibition might be associated with renal function reserve in chronic diabetic kidney disease (CDKD).…”

Section: Discussionmentioning

confidence: 99%

“…Of the three mechanisms, macroautophagy is the most predominant and complicated intracellular process and is often simply referred to as autophagy. Autophagy initiates with the formation of autophagophores, and the Beclin1-interacting complex that consists of Beclin1 and BCL-2 family proteins is required for the initiation process [21][22][23]. Autophagophores elongate and expand, and the elongation requires two ubiquitin-like conjugation systems: the ATG5-ATG12 conjugation system and the microtubule-associated protein light chain 3 (LC3/ATG8) conjugation system.…”

Section: New Players: Autophagymentioning

confidence: 99%

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Diabetic Nephropathy from RAAS to Autophagy: The Era for New Players

Nakhoul¹,

Nakhoul²,

Nakhoul³

2017

J Clin Exp Nephrol

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Diabetic nephropathy is a leading cause of end-stage renal disease (ESRD) and increased cardiovascular morbidity and mortality worldwide in patients with type 2 diabetes mellitus. The mechanisms behind the pathophysiology of DN are complex and continue to be not fully understood. Both metabolic (hyperglycaemia) and haemodynamic alterations interact synergistically, and have been reported to activate local RAAS resulting in increased angiotensin-2. In spite the early and chronic treatment with converting enzyme inhibitors and angiotensin receptor blocking drugs, the number of patients reaching end stage renal disease and replacement therapy are increasing.Recently different pathways were proposed to be involved in the pathogenesis of diabetic nephropathy, including the autophagy process, Klotho and the selective agonist vitamin D and his receptor. Under hyperglycemic stress especially in podocytes and proximal convolute tubule cells, there is decrease in the protective autophagic process and increase in cellular damage.α-Klotho is a multifunctional protein highly expressed in the kidney. The klotho protein has endogenous anti fibrotic function via antagonism of Wnt/β-catenin signaling, which promotes fibrogenesis, suggesting that loss of Klotho in early stage of diabetic nephropathy may contribute to the progression of DN by accelerated fibrogenesis.The selective vitamin D agonist and his receptor, play a protective pathway in diabetic nephropathy. A key renoprotective function of vitamin D is to reduce albuminuria or proteinuria, major risk factors for CKD progression, renal failure, cardiovascular events, and death. This antiproteinuric effect and the deceleration of DN progression is mediated primarily via the blocking of the renin angiotensin aldosterone system. In this review we will discuss the different new mechanisms involved in diabetic nephropathy and future therapeutic agents like the mTorc1 blocker, Rapamycin, that can upregulate the autophagy process, the new sodium-glucose transport inhibitors and Paricalcitol, the selective active vitamin D.

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Section: Discussionmentioning

confidence: 99%

Section: New Players: Autophagymentioning

confidence: 99%

Diabetic Nephropathy from RAAS to Autophagy: The Era for New Players

Nakhoul¹,

Nakhoul²,

Nakhoul³

2017

J Clin Exp Nephrol

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“…88,89 It was previously reported that mTOR signaling is activated in PKD, and rapamycin was identified as an effective therapeutic agent against cystogenesis in rat and mice PKD models. However, rapamycin (everolimus) was not a successful treatment in clinical trials with PKD patients.…”

Section: Autophagy and Ciliummentioning

confidence: 99%

“…However, rapamycin (everolimus) was not a successful treatment in clinical trials with PKD patients. [88][89][90] The regulation of the mTOR pathway is crucial during cystic development. Epithelial cells lining the cysts expressing mutated PC1 protein have increased levels of cell proliferation and abnormally activated mTOR signaling because of a disrupted interaction between PC1 and tuberin, a product of TSC2 gene, which controls mTOR activity.…”

Section: Autophagy and Ciliummentioning

confidence: 99%

Autophagy and regulation of cilia function and assembly

et al. 2014

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Motile and primary cilia (PC) are microtubule-based structures located at the cell surface of many cell types. Cilia govern cellular functions ranging from motility to integration of mechanical and chemical signaling from the environment. Recent studies highlight the interplay between cilia and autophagy, a conserved cellular process responsible for intracellular degradation. Signaling from the PC recruits the autophagic machinery to trigger autophagosome formation. Conversely, autophagy regulates ciliogenesis by controlling the levels of ciliary proteins. The cross talk between autophagy and ciliated structures is a novel aspect of cell biology with major implications in development, physiology and human pathologies related to defects in cilium function. Cell Death and Differentiation (2015) 22, 389-397; doi:10.1038/cdd.2014.171; published online 31 October 2014 FactsAutophagy is a degradative and recycling mechanism that allows cells to adapt to stress situations including nutrient deprivation. Primary cilia (PC) and motile cilia (MC) are sensory structures at the cell surface. PC sense nutrient, growth factor and calcium changes in the extracellular environment and also respond to mechanical stress. MC are beating structures that contribute to innate defense in the lung, for example. The PC is a site for the recruitment of autophagy-related (ATG) proteins that mediate autophagosome formation in response to cilium-dependent signaling. In turn, autophagy regulates the biogenesis of cilia by degrading certain proteins involved in cilia formation. Modulation of autophagy represents a new therapeutic opportunity in diseases related to defective cilia function. Open QuestionsHow are ATG proteins transported to the PC? How do ATG proteins recruited to the PC contribute to the biogenesis of phagophores and autophagosomes? Ciliary proteins are degraded by autophagy. How selective is this degradative pathway? Do some of these proteins contain motifs that result in selective engulfment by autophagosomes?What are the determinants that switch the degradation of ciliary proteins between basal and induced autophagy? Is there any specific function for cilium-dependent autophagy in ciliated cells? Do signals that trigger cilium-dependent autophagy depend on the stimuli (chemical, mechanical) or do all stimuli converge to a single signaling pathway upstream of the autophagy machinery? Can modulation of autophagy contribute to the restoration of cilium functions?Receptors, transporters and specialized plasma membrane structures such as cilia constitute the interfaces between the extracellular and intracellular milieu and allow the cells to trigger specific responses to adapt to changes imposed by the environment. Among these adaptive responses, macroautophagy (hereafter referred to as 'autophagy') is a catabolic process conserved in eukaryotic cells by which the cell recycles its own constituents. 1 Autophagy is involved in the adaptation to starvation, cell differentiation and development, the degradation of aberrant structure...

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“…Progressive autophagy dysfunction can stimulate apoptosis and degeneration in renal cells in IR-induced AKI animals [7]. Thus, the enrichment effects of ω3-PUFAs on autophagy were investigated.…”

Section: Effects Of Endogenous ω3-pufas On Autophagy Fluxmentioning

confidence: 99%

Omega-3 polyunsaturated fatty acids protect against ischemia-reperfusion renal injury through AMPK-mediated autophagy

Dh¹,

Tw²,

J³

et al. 2017

Preprint

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Regulated autophagy is involved in the repair of renal ischemia-reperfusion injury (IRI). ω3-Polyunsaturated fatty acids (ω3-PUFAs) show protective effects against various renal injuries. It was recently reported that ω3-PUFAs regulate autophagy. We assessed whether ω3-PUFAs attenuated IR-induced acute kidney injury (AKI) and evaluated associated mechanisms. C57Bl/6 background fat-1 mice and wild-type mice (wt) were divided into four groups: wt sham (n = 10), fat-1 sham (n = 10), wt IRI (reperfusion 35 min after clamping both the renal artery and vein; n = 15), and fat-1 IRI (n = 15). Kidneys and blood were harvested 24 h after IRI. Renal histological and molecular data were collected. The kidneys of fat-1 mice showed better renal cell survival, renal function, and pathological damage than those of wt mice after IRI. In addition, fat-1 mice showed less oxidative stress and autophagy impairment; greater amounts of LC3, Beclin-1, and Atg7; lower amounts of p62; and higher levels of renal cathepsin D and ATP6E than wt kidneys. They also showed more AMPK activation, which resulted in the inhibition of phosphorylation of the mammalian target of rapamycin (mTOR). Collectively, ω3-PUFAs in fat-1 mice contributed to AMPK mediated autophagy activation, leading to a renoprotective response.

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Autophagy in Kidney Health and Disease

Cited by 88 publications

References 106 publications

Diabetic Nephropathy from RAAS to Autophagy: The Era for New Players

Diabetic Nephropathy from RAAS to Autophagy: The Era for New Players

Autophagy and regulation of cilia function and assembly

Omega-3 polyunsaturated fatty acids protect against ischemia-reperfusion renal injury through AMPK-mediated autophagy

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