Macrophage Wnt7b is critical for kidney repair and regeneration

Lin, Shuei Liong; Li, Bing; Rao, Sujata; Yeo, Eui‐Ju; Hudson, Thomas E.; Nowlin, Brian T.; Hu, Pei; Chen, Lijun; Zheng, Jie; Carroll, Thomas J.; Pollard, Jeffrey W.; McMahon, Andrew P.; Lang, Richard A.; Duffield, Jeremy S.

doi:10.1073/pnas.0912228107

Cited by 371 publications

(402 citation statements)

References 37 publications

(38 reference statements)

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“…Activation of WNT signalling alone induced fibrogenic factors in HRPTC It has been reported that HRPTC are the primary cells that respond to WNT activation after kidney injury [25]. As hyperglycaemia and HNE can trigger multiple signalling pathways [22,[26][27][28][29], in order to confirm the direct effect of WNT activation on renal fibrogenesis in diabetic nephropathy, primary HRPTC were exposed to WNT3A-conditioned medium (WCM); plain L cell conditioned medium (LCM) was used as a control.…”

Section: Resultsmentioning

confidence: 99%

“…Values are expressed as the percentages of the control (Con) values (mean±SD, n=3); *p<0.05. e-h HRPTC were treated with HNE (10 μmol/l) for 6 h. Cytosolic (e, f) and nuclear (g, h) β-catenin levels were measured by western blot analysis using the cytosolic and nuclear fractions, quantified by densitometry from three independent experiments, and normalised to glyceraldehyde-3-phosphate dehydrogenase (GAPDH) levels or histone-3 levels, respectively. Values are expressed as percentages of control values (mean±SD, n=3); *p<0.05 and **p<0.01 been shown to induce overexpression of Wnt1, Wnt2, Wnt2b, Wnt3, Wnt3a, Wnt8a, Wnt16, Fzd3, Fzd4, Fzd9 and Fzd10 gene expression in kidney [14,25], suggesting that the activation of the WNT signalling pathway may be a common pathogenic mechanism for some kidney diseases.…”

Section: Discussionmentioning

confidence: 99%

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Implication of dysregulation of the canonical wingless-type MMTV integration site (WNT) pathway in diabetic nephropathy

et al. 2011

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Aims/hypothesis The wingless-type MMTV integration site (WNT) pathway mediates multiple physiological and pathological processes, such as inflammation, angiogenesis and fibrosis. The aim of this study was to investigate whether canonical WNT signalling plays a role in the pathogenesis of diabetic nephropathy. Methods Expression of WNT ligands and frizzled receptors in the canonical WNT pathway in the kidney was compared at the mRNA level using real-time RT-PCR between Akita mice, streptozotocin-induced diabetic rats and db/db mice and their respective non-diabetic controls. Renal function was evaluated by measuring the urine albumin excretion. Human renal proximal tubular epithelial cells were treated with high-glucose medium and 4-hydroxynonenal (HNE). Levels of β-catenin, connective tissue growth factor and fibronectin were determined by western blot analysis. Results Some of the WNT ligands and frizzled receptors showed increased mRNA levels in the kidneys of Akita mice, streptozotocin-induced diabetic rats and db/db mice compared with their non-diabetic controls. Renal levels of β-catenin and WNT proteins were upregulated in these diabetic models. Lowering the blood glucose levels by insulin attenuated the activation of WNT signalling in the kidneys of Akita mice. In cultured human renal proximal tubular epithelial cells, both high glucose and HNE activated WNT signalling. Inhibition of WNT signalling with a monoclonal antibody blocking LDL-receptor-related protein 6 ameliorated renal inflammation and fibrosis and reduced proteinuria in Akita mice. Conclusions/interpretation The WNT pathway is activated in the kidneys of models of both type 1 and 2 diabetes. Dysregulation of the WNT pathway in diabetes represents a new pathogenic mechanism of diabetic nephropathy and renders a new therapeutic target.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Implication of dysregulation of the canonical wingless-type MMTV integration site (WNT) pathway in diabetic nephropathy

et al. 2011

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“…In some normal adult tissues, Wnt / β -catenin signalling activity has been shown to mainly reside in stem or progenitor cells and to increase upon injury 17,18,49 . Interestingly, stem or progenitor cells are suggested to be fusion partners of transplanted bone marrowderived cells in tissue regeneration, at least in the intestine 3 .…”

Section: Discussionmentioning

confidence: 99%

Identification of a link between Wnt/β-catenin signalling and the cell fusion pathway

et al. 2011

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Cell fusion has a critical role in various developmental processes, immune response, tissue homeostasis and regeneration, and possibly, in cancer. However, the signals that regulate cell fusion remain poorly understood. In a screen for novel targets of Wnt / β -catenin signalling, we identifi ed glial cells missing 1 ( GCM1 ), which encodes a transcription factor that is involved in epigenetic regulation and is critical for the fusion of syncytiotrophoblast (ST) cells. Here we show that β -catenin / BCL9-Like (BCL9L) / T-cell factor 4 (TCF4) signalling directly targets the GCM1 / syncytin pathway and thereby regulates the fusion of human choriocarcinoma cells. Furthermore, we show that the GCM1 / syncytin-B pathway is signifi cantly downregulated in the placenta of BCL9L-defi cient mice and that the fusion and differentiation of ST-II cells are blocked. Our results demonstrate a signal transduction pathway that regulates cell fusion, and may provide intriguing perspectives into the various biological and pathological processes that involve cell fusion.

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“…5,24,[33][34][35] Separately primary proximal tubular epithelial cells were selectively cultured as described. 33,35 Isolation and Culture of Primary Kidney Pericyte…”

Section: Isolation and Culture Of Cells From Kidneymentioning

confidence: 99%

EphrinB2 Reverse Signaling Protects against Capillary Rarefaction and Fibrosis after Kidney Injury

Kida

Ieronimakis

Schrimpf

et al. 2013

Journal of the American Society of Nephrology

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Microvascular disease, a characteristic of acute and chronic kidney diseases, leads to rarefaction of peritubular capillaries (PTCs), promoting secondary ischemic injury, which may be central to disease progression. Bidirectional signaling by EphB4 receptor and ephrinB2 ligand is critical for angiogenesis during murine development, suggesting that ephrinB2 reverse signaling may have a role in renal angiogenesis induced by injury or fibrosis. Here, we found that ephrinB2 reverse signaling is activated in the kidney only after injury. In mice lacking the PDZ intracellular signaling domain of ephrinB2 (ephrinB2 DV), angiogenesis was impaired and kidney injury led to increased PTC rarefaction and fibrosis. EphrinB2 DV primary kidney pericytes migrated more than wild-type pericytes and were less able to stabilize capillary tubes in threedimensional culture and less able to stimulate synthesis of capillary basement membrane. EphrinB2 DV primary kidney microvascular endothelial cells migrated and proliferated less than wild-type microvascular endothelial cells in response to vascular endothelial growth factor A and showed less internalization and activation of vascular endothelial growth factor receptor-2. Taken together, these results suggest that PDZ domain-dependent ephrinB2 reverse signaling protects against PTC rarefaction by regulating angiogenesis and vascular stability during kidney injury. Furthermore, this signaling in kidney pericytes protects against pericyte-to-myofibroblast transition and myofibroblast activation, thereby limiting fibrogenesis.

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Macrophage Wnt7b is critical for kidney repair and regeneration

Cited by 371 publications

References 37 publications

Implication of dysregulation of the canonical wingless-type MMTV integration site (WNT) pathway in diabetic nephropathy

Implication of dysregulation of the canonical wingless-type MMTV integration site (WNT) pathway in diabetic nephropathy

Identification of a link between Wnt/β-catenin signalling and the cell fusion pathway

EphrinB2 Reverse Signaling Protects against Capillary Rarefaction and Fibrosis after Kidney Injury

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