Aberrant Notch1-dependent effects on glomerular parietal epithelial cells promotes collapsing focal segmental glomerulosclerosis with progressive podocyte loss

Ueno, Toshiharu; Kobayashi, Naho; Nakayama, Makiko; Takashima, Yasutoshi; Ohse, Takamoto; Pastan, Ira; Pippin, Jeffrey W.; Shankland, Stuart J.; Uesugi, Noriko; Matsusaka, Taiji; Nagata, Michio

doi:10.1038/ki.2013.48

Cited by 59 publications

(50 citation statements)

References 43 publications

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“…Other potential therapeutic targets for PECs in disease might include epidermal growth factor [48] and its receptor [49], as well as the amino acid transporter LAT2 [50]. More recently, Ueno et al [51] showed that inhibiting Notch in vivo in experimental collapsing FSGS reduced the expression of mesenchymal-like markers including alpha smooth muscle actin, vimentin, and snail.…”

Section: Parietal Epithelial Cells As a Potential Therapeutic Target mentioning

confidence: 99%

Glomerular parietal epithelial cells in kidney physiology, pathology, and repair

Shankland

Anders

Romagnani

2013

Current Opinion in Nephrology and Hypertension

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Purpose of reviewWe have summarized recently published glomerular parietal epithelial cell (PEC) research, focusing on their roles in glomerular development and physiology, and in certain glomerular diseases. The rationale is that PECs have been largely ignored until the recent availability of cell lineage tracing studies, human and murine PEC culture systems, and potential therapeutic interventions of PECs. Recent findingsSeveral new paradigms involving PECs have emerged demonstrating their significant contribution to glomerular physiology and numerous glomerular diseases. A subset of PECs serving as podocyte progenitors have been identified in normal human glomeruli. They provide a source for podocytes in adolescent mice, and their numbers increase in states of podocyte depletion. PEC progenitor number is increased by retinoids and angiotensin-converting enzyme inhibition. However, dysregulated growth of PEC progenitors leads to pseudo-crescent and crescent formation. In focal segmental glomerulosclerosis, considered a podocyte disease, activated PECs increase extracellular matrix production, which leads to synechial attachment and, when they move to the glomerular tuft, to segmental glomerulosclerosis. Finally, PECs might be adversely affected in proteinuric states by undergoing apoptosis. SummaryPECs play a critical role in glomerular repair through their progenitor function, but under certain circumstances paradoxically contribute to deterioration by augmenting scarring and crescent formation.

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Section: Parietal Epithelial Cells As a Potential Therapeutic Target mentioning

confidence: 99%

Glomerular parietal epithelial cells in kidney physiology, pathology, and repair

Shankland

Anders

Romagnani

2013

Current Opinion in Nephrology and Hypertension

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“…Accordingly, inhibition of Notch signaling throughout the regenerative phases led to aggravation of the albuminuria and glomerulosclerosis in a murine model of Adriamycin nephropathy [15]. Furthermore, prolonged Notch blocking in a genetically engineered mouse model of FSGS reduced RPC proliferation and the formation of RPC hyperplastic lesions but worsened podocyte loss and proteinuria [16]. Therefore, a tight regulation of the Notch pathway compensates for a disrupted GFB with progressive podocyte loss.…”

Section: When Regeneration Work: Successful Renal Progenitor Cell DImentioning

confidence: 99%

Glomerular Regeneration: When Can the Kidney Regenerate from Injury and What Turns Failure into Success

Peired

Lazzeri²,

Lasagni³

et al. 2014

Nephron Exp Nephrol

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Background: For many years, the glomerulus was considered incapable of regeneration. However, experimental and clinical evidence challenged this concept and showed that glomerular injury and even glomerulosclerosis can undergo regression under certain circumstances. The problem with glomerular regeneration is centered around the podocyte, a highly specialized cell that is the critical constituent of the glomerular filtration barrier. Summary: Podocytes are characterized by a complex cytoskeleton that makes them unable to proliferate. Thus, once their depletion reaches a specific threshold, it is considered to be irreversible. The discovery of cells with the aptitude to differentiate into podocytes in the adult kidney, i.e. renal progenitor cells (RPCs), was a critical step in understanding the mechanisms of glomerular repair. Accumulating evidence suggests that a tight regulation of many different signaling pathways, such as Notch, Wnt, and microRNA, is involved in a correct regenerative process and that an altered regulation of these same signaling pathways in RPCs triggers the generation of focal segmental glomerulosclerosis lesions. In particular, regeneration is severely impaired by proteinuria, when albumin sequesters retinoic acid and blocks RPC differentiation in podocytes. Key Messages: RPC maintenance and differentiating potential are regulated by complex mechanisms that can be implemented following glomerular injury and can be manipulated to activate regeneration for therapeutic purposes. A better understanding of the phenomenon of glomerular regeneration paves the way for the prevention and treatment of glomerular diseases.

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“…51 Isolated glomeruli were lysed in 0.5% CHAPS buffer. Samples were resolved on SDS-polyacrylamide gels.…”

Section: Western Blottingmentioning

confidence: 99%

Cathepsin D in Podocytes Is Important in the Pathogenesis of Proteinuria and CKD

Yamamoto-Nonaka

Koike²,

Asanuma

et al. 2016

JASN

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Studies have revealed many analogies between podocytes and neurons, and these analogies may be key to elucidating the pathogenesis of podocyte injury. Cathepsin D (CD) is a representative aspartic proteinase in lysosomes. Central nervous system neurons in CD-deficient mice exhibit a form of lysosomal storage disease with a phenotype resembling neuronal ceroid lipofuscinoses. In the kidney, the role of CD in podocytes has not been fully explored. Herein, we generated podocyte-specific CD-knockout mice that developed proteinuria at 5 months of age and ESRD by 20-22 months of age. Immunohistochemical analysis of these mice showed apoptotic podocyte death followed by proteinuria and glomerulosclerosis with aging. Using electron microscopy, we identified, in podocytes, granular osmiophilic deposits (GRODs), autophagosome/autolysosome-like bodies, and fingerprint profiles, typical hallmarks of CDdeficient neurons. CD deficiency in podocytes also led to the cessation of autolysosomal degradation and accumulation of proteins indicative of autophagy impairment and the mitochondrial ATP synthase subunit c accumulation in the GRODs, again similar to changes reported in CD-deficient neurons. Furthermore, both podocin and nephrin, two essential components of the slit diaphragm, translocated to Rab7-and lysosome-associated membrane glycoprotein 1-positive amphisomes/autolysosomes that accumulated in podocyte cell bodies in podocyte-specific CD-knockout mice. We hypothesize that defective lysosomal activity resulting in foot process effacement caused this accumulation of podocin and nephrin. Overall, our results suggest that loss of CD in podocytes causes autophagy impairment, triggering the accumulation of toxic subunit c-positive lipofuscins as well as slit diaphragm proteins followed by apoptotic cell death.

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Aberrant Notch1-dependent effects on glomerular parietal epithelial cells promotes collapsing focal segmental glomerulosclerosis with progressive podocyte loss

Cited by 59 publications

References 43 publications

Glomerular parietal epithelial cells in kidney physiology, pathology, and repair

Glomerular parietal epithelial cells in kidney physiology, pathology, and repair

Glomerular Regeneration: When Can the Kidney Regenerate from Injury and What Turns Failure into Success

Cathepsin D in Podocytes Is Important in the Pathogenesis of Proteinuria and CKD

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