Hypoxia-preconditioned mesenchymal stem cells prevent renal fibrosis and inflammation in ischemia-reperfusion rats

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Abstract

Background

Mesenchymal stem cells (MSCs) have been reported to promote the regeneration of injured tissue via their paracrine abilities, which are enhanced by hypoxic preconditioning. In this study, we examined the therapeutic efficacy of hypoxia-preconditioned MSCs on renal fibrosis and inflammation in rats with ischemia-reperfusion injury (IRI).

Methods

MSCs derived from rats and humans were incubated in 1% O ₂ conditions (1%O ₂ MSCs) for 24 h. After IRI, 1%O ₂ MSCs or MSCs cultured under normoxic conditions (21%O ₂ MSCs) were injected through the abdominal aorta. At 7 or 21 days post-injection, the rats were sacrificed and their kidneys were analyzed. In in vitro experiments, we examined whether 1%O ₂ MSCs enhanced the ability to produce anti-fibrotic humoral factors using transforming growth factor (TGF)-β1-stimulated HK-2 cells incubated with conditioned medium from MSCs.

Results

Administration of rat 1%O ₂ MSCs (1%O ₂ rMSCs) attenuated renal fibrosis and inflammation more significantly than rat 21%O ₂ MSCs. Notably, human 1%O ₂ MSCs (1%O ₂ hMSCs) also attenuated renal fibrosis to the same extent as 1%O ₂ rMSCs. Flow cytometry showed that 1%O ₂ hMSCs did not change human leukocyte antigen expression. Further in vitro experiments revealed that conditioned medium from 1%O ₂ MSCs further suppressed TGF-β1-induced fibrotic changes in HK-2 cells compared with 21%O ₂ MSCs. Hypoxic preconditioning enhanced vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF) secretion. Interestingly, VEGF knockdown in 1%O ₂ MSCs attenuated HGF secretion and the inhibition of TGF-β1-induced fibrotic changes in HK-2 cells. In addition, VEGF knockdown in 1%O ₂ hMSCs reduced the anti-fibrotic effect in IRI rats.

Conclusions

Our results indicate that hypoxia-preconditioned MSCs are useful as an allogeneic transplantation cell therapy to prevent renal fibrosis and inflammation.

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Most cited references 39

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Chronic hypoxia and tubulointerstitial injury: a final common pathway to end-stage renal failure.

Masaomi Nangaku (2006)

Recent studies emphasize the role of chronic hypoxia in the tubulointerstitium as a final common pathway to end-stage renal failure. When advanced, tubulointerstitial damage is associated with the loss of peritubular capillaries. Associated interstitial fibrosis impairs oxygen diffusion and supply to tubular and interstitial cells. Hypoxia of tubular cells leads to apoptosis or epithelial-mesenchymal transdifferentiation. This in turn exacerbates fibrosis of the kidney and subsequent chronic hypoxia, setting in train a vicious cycle whose end point is ESRD. A number of mechanisms that induce tubulointerstitial hypoxia at an early stage have been identified. Glomerular injury and vasoconstriction of efferent arterioles as a result of imbalances in vasoactive substances decrease postglomerular peritubular capillary blood flow. Angiotensin II not only constricts efferent arterioles but, via its induction of oxidative stress, also hampers the efficient utilization of oxygen in tubular cells. Relative hypoxia in the kidney also results from increased metabolic demand in tubular cells. Furthermore, renal anemia hinders oxygen delivery. These factors can affect the kidney before the appearance of significant pathologic changes in the vasculature and predispose the kidney to tubulointerstitial injury. Therapeutic approaches that target the chronic hypoxia should prove effective against a broad range of renal diseases. Current modalities include the improvement of anemia with erythropoietin, the preservation of peritubular capillary blood flow by blockade of the renin-angiotensin system, and the use of antioxidants. Recent studies have elucidated the mechanism of hypoxia-induced transcription, namely that prolyl hydroxylase regulates hypoxia-inducible factor. This has given hope for the development of novel therapeutic approaches against this final common pathway.

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Analysis of the Global Burden of Disease study highlights the global, regional, and national trends of chronic kidney disease epidemiology from 1990 to 2016

Cheng-You Tsai, Tasheia Floyd, Geetha Maddukuri … (2018)

The last quarter century witnessed significant population growth, aging, and major changes in epidemiologic trends, which may have shaped the state of chronic kidney disease (CKD) epidemiology. Here, we used the Global Burden of Disease study data and methodologies to describe the change in burden of CKD from 1990 to 2016 involving incidence, prevalence, death, and disability-adjusted-life-years (DALYs). Globally, the incidence of CKD increased by 89% to 21,328,972 (uncertainty interval 19,100,079- 23,599,380), prevalence increased by 87% to 275,929,799 (uncertainty interval 252,442,316-300,414,224), death due to CKD increased by 98% to 1,186,561 (uncertainty interval 1,150,743-1,236,564), and DALYs increased by 62% to 35,032,384 (uncertainty interval 32,622,073-37,954,350). Measures of burden varied substantially by level of development and geography. Decomposition analyses showed that the increase in CKD DALYs was driven by population growth and aging. Globally and in most Global Burden of Disease study regions, age-standardized DALY rates decreased, except in High-income North America, Central Latin America, Oceania, Southern Sub-Saharan Africa, and Central Asia, where the increased burden of CKD due to diabetes and to a lesser extent CKD due to hypertension and other causes outpaced burden expected by demographic expansion. More of the CKD burden (63%) was in low and lower-middle-income countries. There was an inverse relationship between age-standardized CKD DALY rate and health care access and quality of care. Frontier analyses showed significant opportunities for improvement at all levels of the development spectrum. Thus, the global toll of CKD is significant, rising, and unevenly distributed; it is primarily driven by demographic expansion and in some regions a significant tide of diabetes. Opportunities exist to reduce CKD burden at all levels of development.

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Acute kidney injury increases risk of ESRD among elderly.

Areef Ishani, Jay L Xue, Jonathan Himmelfarb … (2009)

Risk for ESRD among elderly patients with acute kidney injury (AKI) has not been studied in a large, representative sample. This study aimed to determine incidence rates and hazard ratios for developing ESRD in elderly individuals, with and without chronic kidney disease (CKD), who had AKI. In the 2000 5% random sample of Medicare beneficiaries, clinical conditions were identified using Medicare claims; ESRD treatment information was obtained from ESRD registration during 2 yr of follow-up. Our cohort of 233,803 patients were hospitalized in 2000, were aged > or = 67 yr on discharge, did not have previous ESRD or AKI, and were Medicare-entitled for > or = 2 yr before discharge. In this cohort, 3.1% survived to discharge with a diagnosis of AKI, and 5.3 per 1000 developed ESRD. Among patients who received treatment for ESRD, 25.2% had a previous history of AKI. After adjustment for age, gender, race, diabetes, and hypertension, the hazard ratio for developing ESRD was 41.2 (95% confidence interval [CI] 34.6 to 49.1) for patients with AKI and CKD relative to those without kidney disease, 13.0 (95% CI 10.6 to 16.0) for patients with AKI and without previous CKD, and 8.4 (95% CI 7.4 to 9.6) for patients with CKD and without AKI. In summary, elderly individuals with AKI, particularly those with previously diagnosed CKD, are at significantly increased risk for ESRD, suggesting that episodes of AKI may accelerate progression of renal disease.

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Author and article information

Contributors

Ayumu Nakashima: ayumu@hiroshima-u.ac.jp

Takao Masaki: masakit@hiroshima-u.ac.jp

Journal

Journal ID (nlm-ta): Stem Cell Res Ther

Journal ID (iso-abbrev): Stem Cell Res Ther

Title: Stem Cell Research & Therapy

Publisher: BioMed Central (London )

ISSN (Electronic): 1757-6512

Publication date (Electronic): 20 March 2020

Publication date PMC-release: 20 March 2020

Publication date Collection: 2020

Volume: 11

Electronic Location Identifier: 130

Affiliations

[1 ]GRID grid.470097.d, ISNI 0000 0004 0618 7953, Department of Nephrology, , Hiroshima University Hospital, ; 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551 Japan

[2 ]GRID grid.257022.0, ISNI 0000 0000 8711 3200, Department of Stem Cell Biology and Medicine, Graduate School of Biomedical & Health Sciences, , Hiroshima University, ; 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8553 Japan

[3 ]TWOCELLS Company, Limited, 16-35 Hijiyama-honmachi, Minami-ku, Hiroshima, 732-0816 Japan

Article

Publisher ID: 1642

DOI: 10.1186/s13287-020-01642-6

PMC ID: 7083035

PubMed ID: 32197638

SO-VID: 050563da-ef54-487c-9138-36fde91c04f6

License:

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

History

Date received : 1 November 2019

Date revision received : 12 February 2020

Date accepted : 10 March 2020

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100001691, Japan Society for the Promotion of Science;

Award ID: JP17K09699

Award Recipient : Ayumu Nakashima

Custom metadata

ScienceOpen disciplines: Molecular medicine

Keywords: mesenchymal stem cells,hypoxia,vascular endothelial growth factor,hepatocyte growth factor,renal fibrosis

Data availability:

ScienceOpen disciplines: Molecular medicine

Keywords: mesenchymal stem cells, hypoxia, vascular endothelial growth factor, hepatocyte growth factor, renal fibrosis

Hypoxia-preconditioned mesenchymal stem cells prevent renal fibrosis and inflammation in ischemia-reperfusion rats

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Abstract

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Conclusions

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Stress signalling in stem cells

Most cited references 39

Chronic hypoxia and tubulointerstitial injury: a final common pathway to end-stage renal failure.

Analysis of the Global Burden of Disease study highlights the global, regional, and national trends of chronic kidney disease epidemiology from 1990 to 2016

Acute kidney injury increases risk of ESRD among elderly.

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