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Endothelial progenitor cells restore renal function in chronic experimental renovascular disease.

ABSTRACT: Endothelial progenitor cells (EPCs) promote neovascularization and endothelial repair. Renal artery stenosis (RAS) may impair renal function by inducing intrarenal microvascular injury and remodeling. We investigated whether replenishment with EPCs would protect the renal microcirculation in chronic experimental renovascular disease.Single-kidney hemodynamics and function were assessed with the use of multidetector computed tomography in vivo in pigs with RAS, pigs with RAS 4 weeks after intrarenal infusion of autologous EPCs, and controls. Renal microvascular remodeling and angiogenic pathways were investigated ex vivo with the use of micro-computed tomography, histology, and Western blotting. EPCs increased renal expression of angiogenic factors, stimulated proliferation and maturation of new vessels, and attenuated renal microvascular remodeling and fibrosis in RAS. Furthermore, EPCs normalized the blunted renal microvascular and filtration function.The present study shows that a single intrarenal infusion of autologous EPCs preserved microvascular architecture and function and decreased microvascular remodeling in experimental chronic RAS. It is likely that restoration of the angiogenic cascade by autologous EPCs involved not only generation of new vessels but also acceleration of their maturation and stabilization. This contributed to preserving the blood supply, hemodynamics, and function of the RAS kidney, supporting EPCs as a promising therapeutic intervention for preserving the kidney in renovascular disease.

SUBMITTER: Chade AR

PROVIDER: S-EPMC2758066 | biostudies-literature | 2009 Feb

REPOSITORIES: biostudies-literature

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Endothelial progenitor cells restore renal function in chronic experimental renovascular disease.

Chade Alejandro R AR Zhu Xiangyang X Lavi Ronit R Krier James D JD Pislaru Sorin S Simari Robert D RD Napoli Claudio C Lerman Amir A Lerman Lilach O LO

Circulation 20090119 4

<h4>Background</h4>Endothelial progenitor cells (EPCs) promote neovascularization and endothelial repair. Renal artery stenosis (RAS) may impair renal function by inducing intrarenal microvascular injury and remodeling. We investigated whether replenishment with EPCs would protect the renal microcirculation in chronic experimental renovascular disease.<h4>Methods and results</h4>Single-kidney hemodynamics and function were assessed with the use of multidetector computed tomography in vivo in pig ...[more]

PMID: 19153272

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Project description:BackgroundEndothelial dysfunction, characterized by diminished endothelial progenitor cell (EPC) function and flow-mediated vasodilation (FMD), is a clinically significant feature of heart failure (HF). Mesenchymal stem cells (MSCs), which have pro-angiogenic properties, have the potential to restore endothelial function. Accordingly, we tested the hypothesis that MSCs increase EPC function and restore flow-mediated vasodilation (FMD).MethodsIdiopathic dilated and ischemic cardiomyopathy patients were randomly assigned to receive autologous (n = 7) or allogeneic (n = 15) MSCs. We assessed EPC-colony forming units (EPC-CFUs), FMD, and circulating levels of vascular endothelial growth factor (VEGF) in patients before and three months after MSC transendocardial injection (n = 22) and in healthy controls (n = 10).FindingsEPC-colony forming units (CFUs) were markedly reduced in HF compared to healthy controls (4 ± 3 vs. 25 ± 16 CFUs, P < 0.0001). Similarly, FMD% was impaired in HF (5.6 ± 3.2% vs. 9.0 ± 3.3%, P = 0.01). Allogeneic, but not autologous, MSCs improved endothelial function three months after treatment (Δ10 ± 5 vs. Δ1 ± 3 CFUs, P = 0.0067; Δ3.7 ± 3% vs. Δ-0.46 ± 3% FMD, P = 0.005). Patients who received allogeneic MSCs had a reduction in serum VEGF levels three months after treatment, while patients who received autologous MSCs had an increase (P = 0.0012), and these changes correlated with the change in EPC-CFUs (P < 0.0001). Lastly, human umbilical vein endothelial cells (HUVECs) with impaired vasculogenesis due to pharmacologic nitric oxide synthase inhibition, were rescued by allogeneic MSC conditioned medium (P = 0.006).InterpretationThese findings reveal a novel mechanism whereby allogeneic, but not autologous, MSC administration results in the proliferation of functional EPCs and improvement in vascular reactivity, which in turn restores endothelial function towards normal in patients with HF. These findings have significant clinical and biological implications for the use of MSCs in HF and other disorders associated with endothelial dysfunction.

Project description:Background: Chronic kidney disease (CKD) is a global public health problem. Cell therapy using pluripotent stem cells represents an attractive therapeutic approach for the treatment of CKD.Methods: We transplanted mitomycin C (MMC)-treated human induced pluripotent stem cells (hiPSCs) and renal progenitor cells (RPCs) into a CKD rat model system. The RPC and hiPSC cells were characterized by immunofluorescence and qRT-PCR. Untreated 5/6 nephrectomized rats were compared to CKD animals receiving the same amount of MMC-treated hiPSCs or RPCs. Renal function, histology, and immunohistochemistry were evaluated 45?days post-surgery.Results: We successfully generated hiPSCs from peripheral blood and differentiated them into RPCs expressing renal progenitor genes (PAX2, WT1, SIX2, and SALL1) and podocyte-related genes (SYNPO, NPHS1). RPCs also exhibited reduced OCT4 expression, confirming the loss of pluripotency. After cell transplantation into CKD rats, the body weight change was significantly increased in both hiPSC and RPC groups, in comparison with the control group. Creatinine clearance (CCr) was preserved only in the hiPSC group. Similarly, the number of macrophages in the kidneys of the hiPSC group reached a statistically significant reduction, when compared to control rats. Both treatments reduced positive staining for the marker ?-smooth muscle actin. Histological features showed decreased tubulointerstitial damage (interstitial fibrosis and tubular atrophy) as well as a reduction in glomerulosclerosis in both iPSC and RPC groups.Conclusions: In conclusion, we describe that both MMC-treated hiPSCs and RPCs exert beneficial effects in attenuating CKD progression. Both cell types were equally efficient to reduce histological damage and weight loss caused by CKD. hiPSCs seem to be more efficient than RPCs, possibly due to a paracrine effect triggered by hiPSCs. These results demonstrate that the use of MMC-treated hiPSCs and RPCs improves clinical and histological CKD parameters, avoided tumor formation, and therefore may be a promising cell therapy strategy for CKD.

Project description:AimsThe mechanisms responsible for renal injury in atherosclerotic renovascular disease (ARVD) are incompletely understood, and few therapeutic options are available to reverse it. We hypothesized that chronic renal damage involves mitochondrial injury, and that mitochondrial protection would reduce renal fibrosis and dysfunction in ARVD pigs.Methods and resultsDomestic pigs were studied after 10 weeks of ARVD or sham, treated for the last 4 weeks with daily subcutaneous injections (5 days/week) of vehicle or Bendavia (0.1 mg/kg), a tetrapeptide that preserves cardiolipin content in the mitochondrial inner membrane. Single-kidney haemodynamics and function were studied using fast-computer tomography, oxygenation using blood oxygen level-dependent magnetic resonance imaging, microvascular architecture, oxidative stress, and fibrosis ex vivo. Cardiolipin content was assessed using mass spectrometry and staining. Renal endothelial function was studied in vivo and ex vivo. In addition, swine renal artery endothelial cells incubated with tert-butyl hydroperoxide were also treated with Bendavia. Stenotic-kidney renal blood flow (RBF) and glomerular filtration rate (GFR) decreased in ARVD + Vehicle compared with normal (318.8 ± 61.0 vs. 553.8 ± 82.8 mL/min and 48.0 ± 4.0 vs. 84.0 ± 3.8 mL/min, respectively) associated with loss of cardiolipin, intra-renal microvascular rarefaction, and hypoxia. Bendavia restored cardiolipin content in ARVD and improved vascular density, oxygenation, RBF (535.1 ± 24.9 mL/min), and GFR (86.6 ± 11.2 mL/min). Oxidative stress and fibrosis were ameliorated, and renovascular endothelial function normalized both in vivo and in vitro.ConclusionPreservation of mitochondrial cardiolipin attenuated swine stenotic-kidney microvascular loss and injury, and improved renal oxygenation, haemodynamics, and function. These observations implicate mitochondrial damage in renal deterioration in chronic experimental ARVD, and position the mitochondria as a central therapeutic target.

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Endothelial progenitor cells restore renal function in chronic experimental renovascular disease.

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Endothelial progenitor cells restore renal function in chronic experimental renovascular disease.

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