The Pathogenic Role of Notch Activation in Podocytes

Niranjan, Thiruvur; Murea, Mariana; Suszták, Katalin

doi:10.1159/000209207

Cited by 51 publications

(47 citation statements)

References 109 publications

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“…The histological lesions in these animals resembled FSGS. The timing of Notch expression had a slight effect of the histological FSGS subtype; early (developmental) expression induced collapsing FSGS like lesions whereas expression on adult cells resulted in classic FSGS lesions 84 . Notch seems to not only be sufficient to induce sclerosis of the glomerulus, but also necessary, as genetic deletion of Rbpj from podocytes reduced albuminuria in diabetic mouse models 83 .…”

Section: Notch In Kidney Development and Homeostasismentioning

confidence: 99%

Developmental signalling pathways in renal fibrosis: the roles of Notch, Wnt and Hedgehog

et al. 2016

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Kidney fibrosis is the histological manifestation of functional decline in the kidney. Fibrosis is a reactive process that develops in response to excessive epithelial injury and inflammation. Here, we describe how three key developmental signalling pathways—Notch, Wnt and Hedgehog—are reactivated in response to kidney injury. Although transient activation of these pathways is needed for repair of injured tissue, their sustained activation promotes fibrosis. Excessive Wnt and Notch expression prohibit epithelial differentiation whereas increased Wnt and Hh expression induce fibroblast proliferation and myofibroblastic transdifferentiation. Notch, Wnt and Hedgehog are fundamentally different signalling mechanisms, but their choreographed activation seems to be just as important for fibrosis as it is for embryonic kidney development. Decreasing the activity of Notch, Wnt, or Hh signalling could potentially be a new therapeutic strategy to ameliorate the development of chronic kidney disease.

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Section: Notch In Kidney Development and Homeostasismentioning

confidence: 99%

Developmental signalling pathways in renal fibrosis: the roles of Notch, Wnt and Hedgehog

et al. 2016

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“…These data confirm the hypothesis that CaN activity and Synpo cleavage are essential regulators of the renal filter, further dem- Although CaN signaling is clearly important, it is likely not the sole mediator of injury, as inhibition of other pathways also affects glomerular function. 31 We therefore examined additional signaling pathways in the glomerulus. Rapamycin, an inhibitor of mTOR signaling, regulates glomerular function both in vitro and in vivo 18 -20 and exhibits renoprotective effects in many animal models of renal damage.…”

Section: Can and Synpo Are Critical Early Regulators Of Glomerular Bamentioning

confidence: 99%

Calcium Mediates Glomerular Filtration through Calcineurin and mTORC2/Akt Signaling

Vassiliadis

Bracken

Matthews

et al. 2011

Journal of the American Society of Nephrology

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Alterations to the structure of the glomerular filtration barrier lead to effacement of podocyte foot processes, leakage of albumin, and the development of proteinuria. To better understand the signaling pathways involved in the response of the glomerular filtration barrier to injury, we studied freshly isolated rat glomeruli, which allows for the monitoring and pharmacologic manipulation of early signaling events. Administration of protamine sulfate rapidly damaged the isolated glomeruli, resulting in foot process effacement and albumin leakage. Inhibition of calcium channels and chelation of extracellular calcium reduced protamine sulfateinduced damage, suggesting that calcium signaling plays a critical role in the initial stages of glomerular injury. Calcineurin inhibitors (FK506 and cyclosporine A) and the cathepsin L inhibitor E64 all inhibited protamine sulfate-mediated barrier changes, which suggests that calcium signaling acts, in part, through calcineurin-and cathepsin L-dependent cleavage of synaptopodin, a regulator of actin dynamics. The mTOR inhibitor rapamycin also protected glomeruli, demonstrating that calcium signaling has additional calcineurinindependent components. Furthermore, activation of Akt through mTOR had a direct role on glomerular barrier integrity, and activation of calcium channels mediated this process, likely independent of phosphoinositide 3-kinase. Taken together, these results demonstrate the importance of calcium and related signaling pathways in the structure and function of the glomerular filtration barrier.

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“…Transgenic expression of cleaved Notch1 fragment in vivo in podo cytes caused severe albuminuria and glomerulosclerosis in animals. Genetic deletion or pharmacological inhibition of Notch signaling -specifically in podocytes -protected mice from albuminuria and glomerular injury (13,16), which indicates that podocyte Notch expression plays a critical role in glomerulosclerosis devel opment. Increased expression of the Notch ligand Jag1 has recent ly been described in the tubulointerstitial compartment of chronic renal disease samples (15) and in a mouse model of TIF (17).…”

Section: Introductionmentioning

confidence: 99%

Epithelial Notch signaling regulates interstitial fibrosis development in the kidneys of mice and humans

et al. 2010

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The Pathogenic Role of Notch Activation in Podocytes

Cited by 51 publications

References 109 publications

Developmental signalling pathways in renal fibrosis: the roles of Notch, Wnt and Hedgehog

Developmental signalling pathways in renal fibrosis: the roles of Notch, Wnt and Hedgehog

Calcium Mediates Glomerular Filtration through Calcineurin and mTORC2/Akt Signaling

Epithelial Notch signaling regulates interstitial fibrosis development in the kidneys of mice and humans

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