Effect of Notch activation on the regenerative response to acute renal failure

Gupta, Sandeep K.; Li, Shunan; Abedin, Md. Joynal; Wang, Lawrence; Schneider, Eric B.; Najafian, Behzad; Rosenberg, Mark E.

doi:10.1152/ajprenal.00451.2009

Cited by 51 publications

(41 citation statements)

References 65 publications

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“…The early improvement in renal function has been reported in other forms of cytotherapy of AKI (23,24), and this early effect has been cited as reflecting a paracrine action (10). The early activity achieved by cell transfer is clearly desirable, for it is more likely to limit renal damage and subsequent progression to chronic renal failure (8,18). The improved renal function was not derived from improved microvascular flow, which remained unmodified by cell transplantation, in agreement with prior reports derived in another cell transfer system (26).…”

Section: Discussionmentioning

confidence: 94%

“…More recent comparative work on AKI and renal ontogeny has uncovered shared mechanisms for reparative tubulogenesis and embryonic tubulogenesis (5,27). Accordingly, factors that participate in kidney development have also being tested on AKI, including bone morphogenetic protein (28), glial cell line-derived neutrophic growth factor (25), and notch pathway ligand DLL4 (8). Current work has demonstrated a strong renal inflammatory component following AKI (14), and some have reported that mediators of inflammation could also be beneficial in AKI (4).…”

mentioning

confidence: 99%

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Intravenous cell therapy for acute renal failure with serum amyloid A protein-reprogrammed cells

Kelly¹,

Kluve‐Beckerman

Zhang³

et al. 2010

American Journal of Physiology-Renal Physiology

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Section: Discussionmentioning

confidence: 94%

mentioning

confidence: 99%

Intravenous cell therapy for acute renal failure with serum amyloid A protein-reprogrammed cells

Kelly¹,

Kluve‐Beckerman

Zhang³

et al. 2010

American Journal of Physiology-Renal Physiology

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“…There are several examples of developmental signaling pathways that are reactivated in the adult descendants of progenitor cells during injury. Fibroblast growth factor-7, 54 the notch pathway, 55 and Gli1 re-expression 1 are examples of developmental pathways being reactivated during injury in the adult. Wnt4 is expressed in epithelial progenitors during development and is required for tubulogenesis, and Wnt4 is also expressed developmentally in medullary stroma.…”

Section: Discussionmentioning

confidence: 99%

Wnt4/β−Catenin Signaling in Medullary Kidney Myofibroblasts

DiRocco

Kobayashi

Taketo

et al. 2013

Journal of the American Society of Nephrology

159

136

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Injury to the adult kidney induces a number of developmental genes thought to regulate repair, including Wnt4. During kidney development, early nephron precursors and medullary stroma both express Wnt4, where it regulates epithelialization and controls smooth muscle fate, respectively. Expression patterns and roles for Wnt4 in the adult kidney, however, remain unclear. In this study, we used reporters, lineage analysis, and conditional knockout or activation of the Wnt/b-catenin pathway to investigate Wnt4 in the adult kidney. Proliferating, medullary, interstitial myofibroblasts strongly expressed Wnt4 during renal fibrosis, whereas tubule epithelia, except for the collecting duct, did not. Exogenous Wnt4 drove myofibroblast differentiation of a pericyte-like cell line, suggesting that Wnt4 might regulate pericyte-to-myofibroblast transition through autocrine signaling. However, conditional deletion of Wnt4 in interstitial cells did not reduce myofibroblast proliferation, cell number, or myofibroblast gene expression during fibrosis. Because the injured kidney expresses multiple Wnt ligands that might compensate for the absence of Wnt4, we generated a mouse model with constitutive activation of canonical Wnt/b-catenin signaling in interstitial pericytes and fibroblasts. Kidneys from these mice exhibited spontaneous myofibroblast differentiation in the absence of injury. Taken together, Wnt4 expression in renal fibrosis defines a population of proliferating medullary myofibroblasts. Although Wnt4 may be dispensable for myofibroblast transformation, canonical Wnt signaling through b-catenin stabilization is sufficient to drive spontaneous myofibroblast differentiation in interstitial pericytes and fibroblasts, emphasizing the importance of this pathway in renal fibrosis.

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“…The Notch pathway-regulated gene expression occurs in both developing and adult kidneys, and Notch signaling pathways are activated in the adult kidney after injury. 10 Recent studies have documented that Hes protein induced by activation of Notch receptor signaling pathways may function as a nonreceptor scaffold protein in the nucleus that can recruit and allow Janus kinase 2 (JAK2) to phosphorylate signal transducers and activators of transcription 3 (STAT3), thereby leading to activation of an STAT3 signaling pathway. 11 Survivin, which is the smallest member of the inhibitor of apoptosis proteins family, is a 16.5 kDa intracellular protein that has been implicated in regulation of apoptosis, cell division, and cell cycle in cancer cells as well as normal tissues through caspasedependent and -independent mechanisms.…”

mentioning

confidence: 99%

Survivin Mediates Renal Proximal Tubule Recovery from AKI

Chen

Conway

et al. 2013

Journal of the American Society of Nephrology

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AKI induces the renoprotective upregulation of survivin expression in kidney epithelial cells, but the underlying mechanisms have not been identified. To determine the role of survivin in renal recovery from AKI, we generated mice with renal proximal tubule-specific deletion of survivin (survivin ptKO ). Renal survivin expression increased substantially in response to ischemia-reperfusion (I/R) injury in control littermates but remained minimal in survivin ptKO mice. Functional and histologic data indicated similar degrees of renal injury in survivin ptKO and control mice 24 hours after reperfusion, but recovery was markedly delayed in survivin ptKO mice. In MCT cells, a mouse renal proximal tubule cell line, ATP depletion by antimycin A treatment upregulated survivin expression through a phospho-STAT3-dependent pathway. In wild-type mice, inhibition of STAT3 kinase diminished I/R-induced upregulation of STAT3 phosphorylation and survivin expression and delayed recovery. Furthermore, I/R injury activated Notch-2 signaling, and a g-secretase inhibitor suppressed I/R-induced Notch-2 signaling, STAT3 phosphorylation, and survivin expression and delayed recovery. In MCT cells, inhibition of g-secretase similarly attenuated antimycin A-induced Notch-2 activation, upregulation of survivin, and phosphorylation of STAT3, but STAT3 kinase inhibition did not prevent Notch-2 activation. Therefore, these data suggest that STAT3 phosphorylation and subsequent upregulation of survivin expression mediated by Notch-2 signaling in renal proximal tubule epithelial cells aid in the functional and structural recovery of the kidney from AKI. AKI is a common clinical condition encountered in both hospital and outpatient settings, and it is an important cause of morbidity and mortality. Approximately 600,000 cases of AKI are reported each year in the United States. 1 Despite significant preclinical and clinical research, supportive therapy remains the only treatment option for AKI patients, and to date, the mortality rates of AKI remain high. 2 It has also become increasingly clear that AKI is associated with the development of CKD. 3,4 Ischemia-reperfusion (I/R) injury is one of the most common causes of AKI in clinical practice, and the underlying pathogenesis involves injury to nephron segments from both the ischemia itself and the resulting inflammatory response. The S3 segment of proximal tubules is most vulnerable to I/R injury. 5 As a result of I/R injury, renal proximal tubule cells exhibit mitochondrial dysfunction, ATP depletion, impaired solute and ion transport, loss of cell polarity, and cytoskeletal disruption, 6 and they may ultimately undergo apoptosis or necrosis.The kidney has a remarkable capacity for regeneration, which is evidenced by the ability to recover renal function after moderate I/R injury.

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Effect of Notch activation on the regenerative response to acute renal failure

Cited by 51 publications

References 65 publications

Intravenous cell therapy for acute renal failure with serum amyloid A protein-reprogrammed cells

Intravenous cell therapy for acute renal failure with serum amyloid A protein-reprogrammed cells

Wnt4/β−Catenin Signaling in Medullary Kidney Myofibroblasts

Survivin Mediates Renal Proximal Tubule Recovery from AKI

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