The Notch pathway in podocytes plays a role in the development of glomerular disease

Niranjan, Thiruvur; Bielesz, Bernhard; Gruenwald, Antje; Ponda, Manish P.; Kopp, Jeffrey B.; Thomas, David B.; Suszták, Katalin

doi:10.1038/nm1731

Cited by 367 publications

(445 citation statements)

References 45 publications

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“…1a). A previous report showed Notch activation in a diabetic mouse model and in puromycin aminonucleoside (PAN)-treated rats 14 . First, we examined the Notch activation in mice with ADR nephropathy.…”

Section: Resultsmentioning

confidence: 99%

“…The functions of Notch pathway in glomerular diseases remain mostly unclear. So far, two reports evaluated the blockade of Notch pathway using GSI in a rodent model of nephrotic syndrome or genetic engineering in mice 14,27 . Interestingly, they demonstrated the opposite results.…”

Section: Discussionmentioning

confidence: 99%

“…Afterward, Notch pathway becomes silent in matured glomeruli 12,13 . Niranjan et al 14 recently reported that Notch1 was reactivated in kidney specimens of patients with diabetic nephropathy and with focal segmental glomerulosclerosis (FSGS) and that reactivation of Notch1 correlated with the development of proteinuria and glomerulosclerosis due to podocyte apoptosis in rodent models of glomerular disease. Since then, Notch pathway has attracted our attention as a target of new treatment.…”

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confidence: 99%

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Notch2 activation ameliorates nephrosis

et al. 2014

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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Notch2 activation ameliorates nephrosis

et al. 2014

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“…This was driven by a Notch-mediated downregulation of the cell cycle inhibitors p21 and p27, which forces progression toward mitosis of a cell that cannot assemble an efficient mitotic spindle, because it poorly expresses Aurora kinase B [75]. Interestingly, Notch expression is virtually absent in glomeruli of healthy adult kidneys, while several studies demonstrated strong Notch upregulation in podocytes of patients affected by several types of glomerular disorders characterized by podocyte death [75, 77, 78]. In addition, persistent activation of Notch in podocytes leads to podocyte loss and FSGS [75].…”

Section: The Podocyte’s Catastrophe: Lost Cell Cycle Controlmentioning

confidence: 99%

Podocyte Mitosis – A Catastrophe

Lasagni

Lazzeri²,

Shankland

et al. 2012

CMM

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Podocyte loss plays a key role in the progression of glomerular disorders towards glomerulosclerosis and chronic kidney disease. Podocytes form unique cytoplasmic extensions, foot processes, which attach to the outer surface of the glomerular basement membrane and interdigitate with neighboring podocytes to form the slit diaphragm. Maintaining these sophisticated structural elements requires an intricate actin cytoskeleton. Genetic, mechanic, and immunologic or toxic forms of podocyte injury can cause podocyte loss, which causes glomerular filtration barrier dysfunction, leading to proteinuria. Cell migration and cell division are two processes that require a rearrangement of the actin cytoskeleton; this rearrangement would disrupt the podocyte foot processes, therefore, podocytes have a limited capacity to divide or migrate. Indeed, all cells need to rearrange their actin cytoskeleton to assemble a correct mitotic spindle and to complete mitosis. Podocytes, even when being forced to bypass cell cycle checkpoints to initiate DNA synthesis and chromosome segregation, cannot complete cytokinesis efficiently and thus usually generate aneuploid podocytes. Such aneuploid podocytes rapidly detach and die, a process referred to as mitotic catastrophe. Thus, detached or dead podocytes cannot be adequately replaced by the proliferation of adjacent podocytes. However, even glomerular disorders with severe podocyte injury can undergo regression and remission, suggesting alternative mechanisms to compensate for podocyte loss, such as podocyte hypertrophy or podocyte regeneration from resident renal progenitor cells. Together, mitosis of the terminally differentiated podocyte rather accelerates podocyte loss and therefore glomerulosclerosis. Finding ways to enhance podocyte regeneration from other sources remains a challenge goal to improve the treatment of chronic kidney disease in the future.

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“…Indeed, the inappropriate activity of developmental pathways can be causative of renal disease. Niranjan et al [13] report that over-activity of the Notch pathway in podocytes can lead to apoptosis and resultant proteinuria, while genetic or biochemical suppression of this pathway, which is known to be critical for normal proximal tubular development [14,15], prevents glomerulosclerosis and proteinuria.…”

Section: Renal Repair Recapitulating Development: Yes or No?mentioning

confidence: 99%

Stem cell options for kidney disease

Hopkins

Rae

et al. 2008

The Journal of Pathology

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Chronic kidney disease (CKD) is increasing at the rate of 6-8% per annum in the US alone. At present, dialysis and transplantation remain the only treatment options. However, there is hope that stem cells and regenerative medicine may provide additional regenerative options for kidney disease. Such new treatments might involve induction of repair using endogenous or exogenous stem cells or the reprogramming of the organ to reinitiate development. This review addresses the current state of understanding with respect to the ability of non-renal stem cell sources to influence renal repair, the existence of endogenous renal stem cells and the biology of normal renal repair in response to damage. Understanding repair options via an understanding of renal developmentThe prevalence and incidence of chronic kidney disease (CKD) is increasing at 6-8% per annum in the USA alone, largely as a result of increased prevalence of diabetes and obesity [1]. To understand what might be possible with respect to cellular therapies or regenerative medicine for the kidney, one first needs to consider what is understood about normal renal development and response to injury. The kidney has been classically regarded as an organ with minimal cellular turnover and no capacity for regeneration. The subsequent identification of stem cells in a number of such organs, including the brain, has challenged this view. However, the dogma remains that the kidney reaches a maximal complement of nephrons and then loses these over time [2]. This dogma is drawn from our understanding of the development of this organ. The progenitor population during developmentThe kidney is mesodermal in origin and develops from two populations derived from intermediate mesoderm, the ureteric bud (UB) and the metanephric mesenchyme (MM). While an even broader potential had been proposed [3], genetic and lineage analyses have confirmed that the MM gives rise to all portions of the nephron other than the collecting ducts and also gives rise to elements of the renal interstitium [4][5][6]. The UB gives rise to the ureter and collecting ducts only. The MM is apparently not homogeneous but forms condensed mesenchyme around the tips of the branching UB. This cap mesenchyme (CM) contains self-renewing progenitors capable of generating all cells of the nephron other than the collecting ducts via an initial mesenchyme-epithelial transition (MET) event throughout the prenatal developmental period [6]. The continued expression of the transcription factor Six2 in CM is required for maintenance of this stem cell population during kidney development [5]. As the UB branches and extends through the MM, individual MET events occur at the underside of each tip to form a new nephron [2]. This nephron endowment therefore proceeds from the centre of the kidney out to the periphery, with the CM stem cell field remaining on the outer edge of the expanding organ. Endowment of new nephrons is restricted to prenatal development in humans, while in rodents it persists only until the imm...

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The Notch pathway in podocytes plays a role in the development of glomerular disease

Cited by 367 publications

References 45 publications

Notch2 activation ameliorates nephrosis

Notch2 activation ameliorates nephrosis

Podocyte Mitosis – A Catastrophe

Stem cell options for kidney disease

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