Abstract MP25: Defining The Role Of Renin Lineage Cells During Regeneration After Release Of Partial Ureteral Obstruction In Neonatal Mice.

Our previous study on a partial unilateral ureteral obstruction (pUUO) model in neonatal mice showed that the release of obstruction halts the progression of kidney damage and leads to a remarkable repair of the kidney with improvement in renal blood flow. In the current study, we aim to understand the role of mural cells of the renin lineage during kidney damage and repair in the neonatal pUUO model. Our results show a marked increase in renin-positive areas in kidneys obstructed for 3W (Sham-3W: 0.70±0.10%, n=3; Obstructed-3W: 1.82±0.43%, n=3). However, relief of obstruction at 1W restored the renin-positive areas to sham levels (Post-release-2W: 0.70±0.09%; n=3). Lineage tracing using Ren1 d Cre;mTmG mice revealed a significant increase in GFP+ cells in the obstructed kidneys, with a decrease post-release. To understand further the dynamic changes in cells of renin lineage due to obstruction, we ablated the renin cells using DTA (Diphtheria toxin subunit A). We crossed the DTA fl/fl mice with Ren1 d -DTA het ;Ren1 d Cre;mTmG mice and performed pUUO in the resultant pups with DTA in the renin cells (DTA+). DTA+ animals showed thinning of the renal vasculature and a 90% reduction in renin-positive area compared to controls [Control: 0.70±0.10% (n=3); DTA+: 0.06±0.03% (n=3)]. In addition, there was no significant increase in the renin-positive area post-obstruction [Sham-3W: 0.06±0.04% (n=3); Obstructed-3W: 0.12±0.05% (n=4); Post-release-2W: 0.08±0.03% (n=4)]. These results indicate that ablation of renin cells abolished the obstruction-mediated surge in the renin expression. However, measurement of interstitial collagen positive area indicated that despite the absence of renin cells, the fibrotic damage due to obstruction recovered remarkably post-release [Collagen positive area: Sham-3W: 3.38±0.67% (n=3) Obstructed-3W: 62.98±31.50% (n=3); Post-release-2W: 10.93±5.46% (n=4)]. Similarly, vascular damage induced by persistent obstruction and recovery following the relief of obstruction was similar between the DTA+ and non-DTA animals. Our results imply that though the renin and renin lineage cells increase in obstructed kidneys, ablation of renin cells does not affect the regeneration capacity of kidneys following the relief of obstruction.

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The Role of Apelin on the Alleviative Effect of Angiotensin Receptor Blocker in Unilateral Ureteral Obstruction-Induced Renal Fibrosis

Nephron Extra ◽

10.1159/000337091 ◽

2012 ◽

Vol 2 (1) ◽

pp. 39-47 ◽

Cited By ~ 12

Author(s):

Masashi Nishida ◽

Yasuko Okumura ◽

Tatsujiro Oka ◽

Kentaro Toiyama ◽

Seiichiro Ozawa ◽

...

Keyword(s):

Ureteral Obstruction ◽

Renal Fibrosis ◽

Angiotensin Receptor Blocker ◽

Unilateral Ureteral Obstruction ◽

Receptor Blocker ◽

Angiotensin Receptor

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Role of Sirolimus in renal tubular apoptosis in response to unilateral ureteral obstruction

International Journal of Medical Sciences ◽

10.7150/ijms.26954 ◽

2018 ◽

Vol 15 (13) ◽

pp. 1433-1442 ◽

Cited By ~ 2

Author(s):

Mei Yang ◽

Yang-yang Zhuang ◽

Wei-wei Wang ◽

Hai-ping Zhu ◽

Yan-jie Zhang ◽

...

Keyword(s):

Ureteral Obstruction ◽

Unilateral Ureteral Obstruction ◽

Renal Tubular

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Abstract 256: Rbp-j Controls the Fate of the Kidney Vasculature

Hypertension ◽

10.1161/hyp.60.suppl_1.a256 ◽

2012 ◽

Vol 60 (suppl_1) ◽

Author(s):

Eugene Lin ◽

Maria Luisa S Sequeira Lopez ◽

Roberto A Gomez

Keyword(s):

Stromal Cells ◽

Mesangial Cells ◽

Notch Signaling Pathway ◽

Renal Vasculature ◽

Arterial Tree ◽

Mural Cells ◽

Vascular Markers ◽

Renal Abnormalities ◽

Glomerular Tuft

Proper assembly of the renal vasculature is essential for post-natal life, and alterations to the renal vasculature are at the root of many types of cardiovascular disease. However, the mechanisms underlying the establishment, assembly and maintenance of the renal blood vessels are poorly understood. We have identified a population of renal stromal cells (marked by their expression of the transcription factor Foxd1) that differentiate to form the mural cells of the kidney arterial tree (excluding endothelial cells) and the glomerular mesangium. We previously demonstrated that RBP-J, the final transcriptional effector of the Notch signaling pathway, controls the phenotype of renin cells which are also derived from the Foxd1 lineage. We therefore hypothesized that RBP-J regulates the differentiation of stromal cells into the mural cells of the kidney arterioles. To answer this question, we deleted RBP-J in the metanephric stromal precursor cells, and found that mutant mice displayed striking kidney abnormalities in early life. Staining for vascular markers showed a significant decrease in the number of arteries and arterioles. Vessel walls were thinner due to a decrease in both the size and number of smooth muscle cells. We also noted a near absence of renin cells, supporting our earlier findings regarding the key role of RBP-J in establishing the differentiated renin cell endowment. These findings were accompanied by delayed nephrogenesis and other renal abnormalities including tubular dilation. In addition, mutant kidneys lacked Foxd1-lineage cells within the glomeruli, resulting in a depletion of mesangial cells and glomerular aneurysms. Thus, we conclude that RBP-J in Foxd1+ stromal cells plays a key role in the development of the kidney vasculature, and regulates the fate of cells that compose the arterial tree and the glomerular tuft.

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Abstract MP123: The Fate and Role of Pericytes in Repair and Remodeling of the Infarcted Heart

Circulation Research ◽

10.1161/res.127.suppl_1.mp123 ◽

2020 ◽

Vol 127 (Suppl_1) ◽

Author(s):

Linda Alex ◽

Ya Su ◽

Nikolaos G Frangogiannis

Keyword(s):

Lineage Tracing ◽

Mrna Levels ◽

Infarct Zone ◽

Subsequent Formation ◽

Mural Cells ◽

Infarcted Heart ◽

Reporter Mice ◽

Ng2 Cells ◽

Migratory Phenotype

Repair of the infarcted heart is dependent on inflammation-driven activation of myofibroblasts (MFs) and subsequent formation of a scar. Though pericytes have been implicated in injury-associated fibroblast activation in several organs, their potential role in cardiac repair and fibrosis has not been studied. We hypothesized that myocardial infarction (MI) may induce pericyte activation, contributing to repair through pericyte to MF conversion, secretion of fibrogenic mediators, or regulation of angiogenesis. In order to test the hypothesis, we generated pericyte/fibroblast reporter mice (NG2 DsRed ;PDGFRα GFP ). In normal myocardium, NG2 labeled peri-endothelial mural cells that coexpressed PDGFRβ, whereas PDGFRα identified interstitial cells with fibroblast characteristics. Pericytes and fibroblasts had distinct transcriptomic profiles: NG2+/PDGFRα- pericytes expressed αSMA and low amounts of extracellular matrix (ECM) genes, whereas PDGFRα+/NG2- fibroblasts synthesized collagens. Pericyte rarefaction was noted in the necrotic core 3 days after non-reperfused MI. 3-7 days post MI, expansion of the NG2+ population in the infarct zone was associated with emergence of non-mural NG2+/αSMA+ cells with MF characteristics. FACS-sorted NG2+/PDGFRα- cells from 7-day infarcts expressed higher levels of ColIα2 (7.2±1.0-fold) and ColIIIα1 (8.9±1.14-fold), when compared to NG2+/PDGFRα- cells from normal hearts. NG2+ cells had high mRNA levels of integrins α1, αV, β1, and β5, and of MMP14, reflecting an activated migratory phenotype. To examine whether expression of ECM genes by infarct pericytes is due to fibroblast conversion, we did lineage tracing studies using NG2CreER TM ;Rosa tdTomato mice bred with the PDGFRα GFP line for reliable fibroblast identification. 7 days post MI, 5.7%±1.04 of PDGFRα+ fibroblasts were derived from NG2+ cells. Also, αSMA staining showed that 10.49%±2.73 of infarct MFs were derived from NG2+ lineage. The majority of mural cells wrapping neovessels were derived from NG2+ cells, suggesting a role for resident pericytes in infarct angiogenesis. In conclusion, upon MI, pericytes become activated and contribute to repair by undergoing conversion to a subset of myofibroblasts and by coating infarct neovessels.

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Potential Role of the Resident Mesenchymal Stem-Like Cells in Renal Fibrogenesis after Ureteral Obstruction

Stem Cells International ◽

10.1155/2019/2543171 ◽

2019 ◽

Vol 2019 ◽

pp. 1-11

Author(s):

Yong-Hua Peng ◽

Jie Xiao ◽

Chen Yan ◽

Lan Luo ◽

Tao-Sheng Li

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Ureteral Obstruction ◽

Potential Role ◽

Histological Analysis ◽

Left Kidney ◽

Inflammatory Cells ◽

Unilateral Ureteral Obstruction ◽

Renal Fibrogenesis

The mechanisms of renal fibrogenesis after ureteral obstruction remain unclear. We tried to primarily expand mesenchymal stem cells from renal tissues and then investigated their role in fibrogenesis after ureteral obstruction. Unilateral ureteral obstruction was induced by ligating the left ureteral duct of adult C57BL/6 mice. We collected the kidneys for experiments at 2, 7, and 14 days after operation. Histological analysis showed obviously fibrotic changes in the left kidney at 7 days and further increased at 14 days after ureteral obstruction. To expand mesenchymal stem cells, we minced the renal tissues into small explants (about 1 mm3) and cultured onto 10 cm dishes. Interestingly, the outgrowth of cells was observed significantly earlier from the explants of the obstructed left kidney than that of the unobstructed right kidney. These expanded cells showed the potency of adipogenic, osteogenic, and chondrogenic differentiations and positively expressed with CD44 and partly expressed with CD90, CD105, and CD106, but negatively expressed with CD34, CD45, and FSP1, suggesting the phenotype of mesenchymal stem-like cells (MSLCs). The mouse fibrosis RT2 profiler PCR array showed that many genes were changed over 2-fold in the MSLCs expanded from both kidneys at 2, 7, and 14 days after operation. Interestingly, profibrotic genes were prevalently enhanced in the left kidney with ureteral obstruction. Histological analysis also showed obviously infiltration of inflammatory cells in the left kidney at 14 days after operation. Our data indicate the potential role of resident MSLCs in renal fibrogenesis after ureteral obstruction, but further experiments are required to understand the relevant mechanisms.

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