Live or Let Die: Is There any Cell Death in Podocytes?

Braun, Fabian; Becker, Jan U.; Brinkkoetter, Paul T.

doi:10.1016/j.semnephrol.2016.03.008

Cited by 13 publications

(12 citation statements)

References 141 publications

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“…Interestingly, we also observed changes in pyroptosis, which is another form of podocyte death. (43) In podocytes from aged mice injected with the aPD1ab, inflammasome genes involved in pyroptosis were significantly downregulated compared to IgG2a 11 control injected aged mice (e.g., Nlrp2: -2.72-fold, Nlrp6: -2.6-fold), Nlrp4: -2.56-fold, Nlrp5: -2.35-fold, Gsdmd: -2.11-fold, Casp1: -2.08-fold, and Nlrp1b: -2.59-fold).…”

Section: Pd-1 Inhibition Restores Apoptosis Pyroptosis Endoplasmic Reticulum Stress and Autophagymentioning

confidence: 99%

Upregulated PD-1 Signaling is an Important Antagonist to Glomerular Health in Aged Kidneys

Pippin

Kaverina

Wang

et al. 2021

Preprint

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Kidney aging and its contribution to disease and its underlying mechanisms are not well understood. With an aging population, kidney health becomes an important medical and socioeconomic factor. We previously showed that podocytes isolated from aged mice exhibit increased expression of Programed Cell Death Protein 1 (PD-1) surface receptor and its two ligands (PD-L1, PD-L2). PDCD1 transcript increases with age in micro-dissected human glomeruli, which correlates with lower eGFR, and higher segmental glomerulosclerosis and vascular arterial intima to lumen ratio. In vitro studies in podocytes demonstrate a critical role for PD-1 signaling in cell survival and induction of a Senescence-Associated Secretory Phenotype (SASP). To prove PD-1 signaling is critical to podocyte aging, aged mice were injected with anti-PD-1 antibody (aPD-1ab). Treatment significantly improved the aging phenotype in both kidney and liver. In the glomerulus, it increased the life-span of podocytes, but not parietal epithelial, mesangial or endothelial cells. Transcriptomic and immunohistochemistry studies demonstrate that anti-PD-1 treatment improved the health-span of podocytes. It restored the expression of canonical podocyte genes, transcription factors and gene regulatory networks, increased cellular metabolism signatures and lessened SASPs. These results suggest a critical contribution for increased PD-1 signaling towards both kidney and liver aging.

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Section: Pd-1 Inhibition Restores Apoptosis Pyroptosis Endoplasmic Reticulum Stress and Autophagymentioning

confidence: 99%

Upregulated PD-1 Signaling is an Important Antagonist to Glomerular Health in Aged Kidneys

Pippin

Kaverina

Wang

et al. 2021

Preprint

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“…The actin cytoskeleton, crucial for maintenance of the specific shape of podocytes, undergoes changes, resulting in morphological alternations, characteristically cell body attenuation, loss of the slit diaphragm, and foot process effacement (Kriz et al 1998 ; Jefferson and Shankland 2014 ; Grahammer et al 2016 ; Schell et al 2017 ; Schell and Huber 2017 ). These changes in cell shape and adhesion precede podocyte detachment from the glomerular basement membrane leading eventually to a reduced podocyte number (Jefferson and Shankland 2014 ; Braun et al 2016 ; Schell et al 2018 ; Puelles et al 2019 ). Besides the development of effacement as the earliest feature of FSGS and its recurrence post-transplant, there are other aspects emphasizing podocyte damage as the initial step in primary FSGS development (Chang et al 2012 ; Alachkar et al 2013 ).…”

Section: Podocytesmentioning

confidence: 99%

Immune-mediated entities of (primary) focal segmental glomerulosclerosis

et al. 2021

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Focal segmental glomerulosclerosis (FSGS) represents a glomerular scar formation downstream of various different mechanisms leading to podocytopathy and podocyte loss. Recently, significant advances were made in understanding genetic factors, podocyte intrinsic mechanisms, and adaptive mechanisms causing FSGS. However, while most cases of nephrotic FSGS are being treated with immunosuppressants, the underlying immune dysregulation, involved immune cells, and soluble factors are only incompletely understood. Thus, we here summarize the current knowledge of proposed immune effector cells, secreted soluble factors, and podocyte response in immune-mediated (primary) FSGS.

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“…Earlier, studies have shown that podocytes undergo apoptosis in response to noxious stimuli. 34 Therefore, we assessed podocyte apoptosis in AGE-treated human podocytes (in vitro) and mice (in vivo). Glomerular sections from mice treated with AGEs showed increased TUNEL positive cells (online supplementary figure S2A), elevated cleaved caspase 3, and Bax expression (online supplementary figure S2B,C).…”

Section: Age-induced Notch1 Signaling Is Abrogated By Rage Inhibitor In Vivomentioning

confidence: 99%

Activation of Notch1 signaling in podocytes by glucose-derived AGEs contributes to proteinuria

Nishad

Meshram

Singh

et al. 2020

BMJ Open Diab Res Care

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IntroductionAdvanced glycation end-products (AGEs) are implicated in the pathogenesis of diabetic nephropathy (DN). Previous studies have shown that AGEs contribute to glomerulosclerosis and proteinuria. Podocytes, terminally differentiated epithelial cells of the glomerulus and the critical component of the glomerular filtration barrier, express the receptor for AGEs (RAGE). Podocytes are susceptible to severe injury during DN. In this study, we investigated the mechanism by which AGEs contribute to podocyte injury.Research design and methodsGlucose-derived AGEs were prepared in vitro. Reactivation of Notch signaling was examined in AGE-treated human podocytes (in vitro) and glomeruli from AGE-injected mice (in vivo) by quantitative reverse transcription-PCR, western blot analysis, ELISA and immunohistochemical staining. Further, the effects of AGEs on epithelial to mesenchymal transition (EMT) of podocytes and expression of fibrotic markers were evaluated.ResultsUsing human podocytes and a mouse model, we demonstrated that AGEs activate Notch1 signaling in podocytes and provoke EMT. Inhibition of RAGE and Notch1 by FPS-ZM1 (N-Benzyl-4-chloro-N-cyclohexylbenzamide) and DAPT (N-[N-(3,5-Difluorophenacetyl)-L-alanyl]-S-phenyl glycine t-butylester), respectively, abrogates AGE-induced Notch activation and EMT. Inhibition of RAGE and Notch1 prevents AGE-induced glomerular fibrosis, thickening of the glomerular basement membrane, foot process effacement, and proteinuria. Furthermore, kidney biopsy sections from people with DN revealed the accumulation of AGEs in the glomerulus with elevated RAGE expression and activated Notch signaling.ConclusionThe data suggest that AGEs activate Notch signaling in the glomerular podocytes. Pharmacological inhibition of Notch signaling by DAPT ameliorates AGE-induced podocytopathy and fibrosis. Our observations suggest that AGE-induced Notch reactivation in mature podocytes could be a novel mechanism in glomerular disease and thus could represent a novel therapeutic target.

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Live or Let Die: Is There any Cell Death in Podocytes?

Cited by 13 publications

References 141 publications

Upregulated PD-1 Signaling is an Important Antagonist to Glomerular Health in Aged Kidneys

Upregulated PD-1 Signaling is an Important Antagonist to Glomerular Health in Aged Kidneys

Immune-mediated entities of (primary) focal segmental glomerulosclerosis

Activation of Notch1 signaling in podocytes by glucose-derived AGEs contributes to proteinuria

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