Inhibition of Notch Signaling Ameliorates Acute Kidney Failure and Downregulates Platelet-Derived Growth Factor Receptor β in the Mouse Model

Kramer, Jan; Schwanbeck, Ralf; Pagel, Horst; Cakiroglu, Figen; Rohwedel, Jürgen; Just, Ursula

doi:10.1159/000442463

Cited by 14 publications

(5 citation statements)

References 38 publications

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“…Blockade of the Notch pathway, by using γ-secretase inhibitor starting at 24h and at 1-2 hrs before ischemia-reperfusion injury, involved less interstitial edema formation, a decreased expression of the Notch receptors (Notch3 and Notch1), its ligands (Delta-like-4 and Jagged-1) and PDGFB leading to a reduction of fibrosis with an amelioration of renal function. These data demonstrate that the severity of kidney injury can be ameliorated by blocking Notch activation through pharmacologic inhibition of Notch activation following AKI [88] ( Figure 2). [89].…”

Section: Hippo and Notch Signaling Pathwaysmentioning

confidence: 72%

Biologic modulation in renal regeneration

Mazzinghi

Romagnani

Lazzeri

2016

Expert Opinion on Biological Therapy

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Introduction: Chronic kidney disease (CKD) is recognized as a health care problem of increasing importance. Following the discovery of renal progenitors, the investigation of new therapeutic approaches to promote the kidney regenerative capacity has received increasing research attention. Areas covered: The authors discuss the current knowledge of glomerular regeneration by renal progenitors and the modulation of their behavior through chemical and biological agents. The regenerative capacity of renal progenitors after injury must be regulated in order to prevent an Downloaded by [Weill Cornell Medical College] at 02:50 05 August 2016 inefficient or excessive response that could lead to a failed attempt to replace lost podocytes. In addition, they discuss the most relevant pathways involved in tubular repair and how these could be modulated in order to obtain renal regeneration rather than progression of a fibrotic maladaptive response. Expert opinion: Further studies are needed to establish the existence of tubular progenitors and their role in driving the tubular response after injury. Modulation of the endogenous renal regenerative capacity is a new approach in the treatment of kidney diseases. Research efforts that concentrate on the potential regenerative capacity of the kidney can be advantageous when the experimental results are translated into clinical practice and may open the way to new therapeutic strategies for CKD.

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Section: Hippo and Notch Signaling Pathwaysmentioning

confidence: 72%

Biologic modulation in renal regeneration

Mazzinghi

Romagnani

Lazzeri

2016

Expert Opinion on Biological Therapy

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“…The Notch family consists of a group of highly conserved proteins including four cognate receptor Notch l-4, 5 types of homolog ligand Delta-like 1, 3 and 4, and Jagged 1 and 2, and two types of downstream target genes: The Hes and Hey families. When tissue is subjected to hypoxia and drug damage, the activation of ligand expression would increase, which can result in the series of proteolytic cleavage of Notch receptors via the Notch receptor binding through cell to cell contact, and then release the Notch intracellular domain of activity; the Notch intracellular domain activity is transferred to the cell nucleus and combined with the transcription factor binding, starting the transcription of the target gene, regulating and controlling the cell proliferation (7,8). …”

Section: Discussionmentioning

confidence: 99%

“…Western blotting was performed as described elsewhere (7). The primary antibody was used for incubation overnight at 4°C.…”

Section: Methodsmentioning

confidence: 99%

The mechanism of blood concentrations of the Shenqi pill repairing injured epithelial cells of renal tubular in vitro

Huang¹,

Ma²

2017

Experimental and Therapeutic Medicine

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In the present study, we investigated the best blood concentration of the mechanism of Shenqi pill repairing the injured epithelial cells of renal tubular in vitro. First, the injured hypoxia/reoxygenation model of rat proximal renal tubular epithelial cell strain (NRK-52E) was established. The animals were divided randomly into control, model, low concentration (5 µg/ml), moderate concentration (10 µg/ml) and high concentration (20 µg/ml) groups. The apoptotic rate was measured with flow cytometry and Jag2/Notch2/hes1 mRNA, and the protein expression was measured for 1, 3 and 7 days. It was found that in comparison to the control group, the growth of each group was prolonged with time, the levels of apoptosis, and the Jag2/Notch2/hes1 mRNA and protein expression decreased. Furthermore, the levels of the apoptotic rate, Jag2/Notch2/hes1 mRNA and protein expression of the moderate concentration and high concentration groups were significantly lower than those of the model and low-dose groups at each time-point (P<0.05). In conclusion, the Shenqi Pill alleviates the damage of renal tubular epithelial cells by inhibiting the Jag2/Notch2/hes1 signaling pathway; suitable concentration such as 10–20 µg/ml can exert protective effect.

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“…In the BMP9 group, OS was induced, and BMP9 overexpressing ADMSCs were injected into the articular cavity. In the LY group, OS was induced, and LY411575 (1.5 µmol/l) ( 28 , 29 ) was injected into the articular cavity to inhibit the Notch signaling pathway, and BMP9 overexpressing ADMSCs were also injected.…”

Section: Methodsmentioning

confidence: 99%

BMP9 overexpressing adipose‑derived mesenchymal stem cells promote cartilage repair in osteoarthritis-affected knee joint via the Notch1/Jagged1 signaling pathway

Du²,

Wang

et al. 2018

Exp Ther Med

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Osteoarthritis (OS) is a common disease in orthopedics. Although OS is known as an inflammation mediated by inflammatory cytokines; however, the mechanism is poorly understood. In the present study, the role of bone morphogenetic protein-9 (BMP9) was investigated in chondrogenic differentiation of adipose-derived mesenchymal stem cells (ADMSCs). ADMSCs were transfected with BMP9. BMP9 mRNA expression was detected by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Type II collagen and aggrecan expression was detected by western blotting and RT-qPCR. Mouse models of knee OS were established. Hematoxylin-eosin staining and toluidine blue staining were performed to observe changes in the OS-affected knee joint. After intra-articular injection of ADMSCs transfected with BMP9, intra-articular expression of type II collagen and aggrecan was detected by western blot analysis and RT-qPCR. After the Notch signaling pathway was inhibited in ADMSCs, ADMSCs were injected into the articular cavity. The expression of Notch signaling pathway-related proteins Notch1 and Jagged1 was detected by western blot analysis and RT-qPCR. BMP9 promoted chondrogenic differentiation of ADMSCs. After injection of BMP9 overexpressing ADMSCs into the articular space, type II collagen and aggrecan expression was increased. When the Notch signaling pathway of ADMSCs was inhibited, the ability of BMP9 overexpressing ADMSCs to repair the cartilage in the OS-affected knee joint was attenuated. These results demonstrate that upregulating BMP9 protein expression may promote the chondrogenic differentiation of ADMSCs. Intra-articular injection of ADMSCs contributes to cartilage repair in OS-affected knee joints through the Notch1/Jagged1 signaling pathway.

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Inhibition of Notch Signaling Ameliorates Acute Kidney Failure and Downregulates Platelet-Derived Growth Factor Receptor β in the Mouse Model

Cited by 14 publications

References 38 publications

Biologic modulation in renal regeneration

Biologic modulation in renal regeneration

The mechanism of blood concentrations of the Shenqi pill repairing injured epithelial cells of renal tubular in vitro

BMP9 overexpressing adipose‑derived mesenchymal stem cells promote cartilage repair in osteoarthritis-affected knee joint via the Notch1/Jagged1 signaling pathway

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