Inhibition of endoplasmic reticulum stress signaling rescues cytotoxicity of human apolipoprotein-L1 risk variants in Drosophila

Gerstner, Lea; Chen, Mengmeng; Kampf, Lina L; Milosavljevic, Julian; Lang, Konrad; Schneider, Ronen; Hildebrandt, Friedhelm; Helmstädter, Martin; Walz, Gerd; Hermle, Tobias

doi:10.1016/j.kint.2021.12.031

Cited by 16 publications

(29 citation statements)

References 53 publications

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“…With mild overexpression, APOL1 G0 cells (not G1 or G2) are relatively resistant to ER stress [38]. Further, ER stress inhibitors reduce cell necrosis in G1 and G2-expressing podocytes [42], and APOL1-dependent ER stress was suppressed in a Drosophila model with Xbp1-RNAi [41 ▪ ]. These data support the idea that reducing ER stress or inducing increased resistance to ER stress in relevant kidney cells could be promising therapies for nephropathy.…”

Section: Novel Therapiessupporting

confidence: 62%

“…Although we do not know the exact mechanism with certainty or have complete information on the relevant cell types, the current thinking that APOL1 -associated nephropathy stems largely from a gain-of-function mechanism suggests that either reduction of APOL1 protein or interference with its activity is likely to ameliorate toxicity. Whether injury is primarily through cell surface channel activity [36,37], mitochondrial dysfunction [38–40], endoplasmic reticulum (ER) stress [41 ▪ ,42] or other proposed mechanisms [43 ▪▪ ,44 ▪▪ ,45], effective therapy may actually precede a full elucidation of mechanistic behaviour of the risk variant protein.…”

Section: Novel Therapiesmentioning

confidence: 99%

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Treatment potential in APOL1-associated nephropathy

Friedman

Freedman

2022

Current Opinion in Nephrology &Amp; Hypertension

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Purpose of reviewMore than 5 million African–Americans, and millions more in Africa and worldwide, possess apolipoprotein L1 gene (APOL1) high-risk genotypes with an increased risk for chronic kidney disease. This manuscript reviews treatment approaches for slowing the progression of APOL1-associated nephropathy.Recent findingsSince the 2010 discovery of APOL1 as a cause of nondiabetic nephropathy in individuals with sub-Saharan African ancestry, it has become apparent that aggressive hypertension control, renin-angiotensin system blockade, steroids and conventional immunosuppressive agents are suboptimal treatments. In contrast, APOL1-mediated collapsing glomerulopathy due to interferon treatment and HIV infection, respectively, often resolve with cessation of interferon or antiretroviral therapy. Targeted therapies, including APOL1 small molecule inhibitors, APOL1 antisense oligonucleotides (ASO) and inhibitors of APOL1-associated inflammatory pathways, hold promise for these diseases. Evolving therapies and the need for clinical trials support the importance of increased use of APOL1 genotyping and kidney biopsy.SummaryAPOL1-associated nephropathy includes a group of related phenotypes that are driven by the same two genetic variants in APOL1. Clinical trials of small molecule inhibitors, ASO, and inflammatory pathway inhibitors may improve outcomes in patients with primary forms of APOL1-associated nephropathy.

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Section: Novel Therapiessupporting

confidence: 62%

Section: Novel Therapiesmentioning

confidence: 99%

Treatment potential in APOL1-associated nephropathy

Friedman

Freedman

2022

Current Opinion in Nephrology &Amp; Hypertension

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“…This indicates that widespread initiation of cell death is the consequence of Tor inhibition and basal mTOR activity seems to promote cell survival in nephrocytes. Since TUNEL positivity may occur in nephrocytes that are still vital and even show functional hypertrophy [39], we utilized a live/dead detection method to determine the fraction of cells with immediately impaired viability after the expression of Tor-RNAi. This assay employs a lack of exclusion of a fixable viability dye resulting in elevated intracellular fluorescence intensity for the identification of dead cells.…”

Section: Manipulation Of Mtor Signaling Affects Nephrocyte Cell Size ...mentioning

confidence: 99%

mTOR-Dependent Autophagy Regulates Slit Diaphragm Density in Podocyte-like Drosophila Nephrocytes

Spitz

Comas

Gerstner

et al. 2022

Cells

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Both mTOR signaling and autophagy are important modulators of podocyte homeostasis, regeneration, and aging and have been implicated in glomerular diseases. However, the mechanistic role of these pathways for the glomerular filtration barrier remains poorly understood. We used Drosophila nephrocytes as an established podocyte model and found that inhibition of mTOR signaling resulted in increased spacing between slit diaphragms. Gain-of-function of mTOR signaling did not affect spacing, suggesting that additional cues limit the maximal slit diaphragm density. Interestingly, both activation and inhibition of mTOR signaling led to decreased nephrocyte function, indicating that a fine balance of signaling activity is needed for proper function. Furthermore, mTOR positively controlled cell size, survival, and the extent of the subcortical actin network. We also showed that basal autophagy in nephrocytes is required for survival and limits the expression of the sns (nephrin) but does not directly affect slit diaphragm formation or endocytic activity. However, using a genetic rescue approach, we demonstrated that excessive, mTOR-dependent autophagy is primarily responsible for slit diaphragm misspacing. In conclusion, we established this invertebrate podocyte model for mechanistic studies on the role of mTOR signaling and autophagy, and we discovered a direct mTOR/autophagy-dependent regulation of the slit diaphragm architecture.

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“…Our findings are consistent with the translational literature suggesting nonglomerular mechanisms for APOL1-mediated kidney damage, including endoplasmic reticular stress, mitochondrial dysfunction, and cytotoxicity resulting in apoptosis and pyroptosis, among others. 18 , 19 , 20 , 21 Future studies should investigate additional mechanisms independent of the development of proteinuria. Although kidney damage from the high-risk APOL1 genotype is mediated in part by the development of proteinuria, kidney damage may occur through a mechanism independent of proteinuria.…”

Section: Discussionmentioning

confidence: 99%