Research Article
No access
Published Online: 1 July 2017

Uremic Toxins Affect the Imbalance of Redox State and Overexpression of Prolyl Hydroxylase 2 in Human Adipose Tissue-Derived Mesenchymal Stem Cells Involved in Wound Healing

Publication: Stem Cells and Development
Volume 26, Issue Number 13

Abstract

Chronic kidney disease (CKD) results in a delay in wound healing because of its complications such as uremia, anemia, and fluid overload. Mesenchymal stem cells (MSCs) are considered to be a candidate for wound healing because of the ability to recruit many types of cells. However, it is still unclear whether the CKD-adipose tissue-derived MSCs (CKD-AT-MSCs) have the same function in wound healing as healthy donor-derived normal AT-MSCs (nAT-MSCs). In this study, we found that uremic toxins induced elevated reactive oxygen species (ROS) expression in nAT-MSCs, resulting in the reduced expression of hypoxia-inducible factor-1α (HIF-1α) under hypoxic conditions. Consistent with the uremic-treated AT-MSCs, there was a definite imbalance of redox state and high expression of ROS in CKD-AT-MSCs isolated from early-stage CKD patients. In addition, a transplantation study clearly revealed that nAT-MSCs promoted the recruitment of inflammatory cells and recovery from ischemia in the mouse flap model, whereas CKD-AT-MSCs had defective functions and the wound healing process was delayed. Of note, the expression of prolyl hydroxylase domain 2 (PHD2) is selectively increased in CKD-AT-MSCs and its inhibition can restore the expression of HIF-1α and the wound healing function of CKD-AT-MSCs. These results indicate that more studies about the functions of MSCs from CKD patients are required before they can be applied in the clinical setting.

Get full access to this article

View all available purchase options and get full access to this article.

References

1.
Tonelli M, Wiebe N, Culleton B, House A, Rabbat C, Fok M, McAlister F and Garg AX. (2006). Chronic kidney disease and mortality risk: a systematic review. J Am Soc Nephrol 17:2034–2047.
2.
Thomas R, Kanso A and Sedor JR. (2008). Chronic kidney disease and its complications. Prim Care 35:329–vii.
3.
Sung CC, Hsu YC, Chen CC, Lin YF and Wu CC. (2013). Oxidative stress and nucleic acid oxidation in patients with chronic kidney disease. Oxid Med Cell Longev 2013:301982.
4.
Maroz N and Simman R. (2013). Wound healing in patients with impaired kidney function. J Am Coll Clin Wound Spec 5:2–7.
5.
Guo S and DiPietro LA. (2010). Factors affecting wound healing. J Dent Res 89:219–229.
6.
Maxson S, Lopez EA, Yoo D, Danilkovitch-Miagkova A and LeRoux MA. (2012). Concise review: role of mesenchymal stem cells in wound repair. Stem Cells Transl Med 1:142–149.
7.
Hocking AM. (2015). The role of chemokines in mesenchymal stem cell homing to wounds. Adv Wound Care 4:623–630.
8.
Nombela-Arrieta C, Ritz J and Silberstein LE. (2011). The elusive nature and function of mesenchymal stem cells. Nat Rev Mol Cell Biol 12:126–131.
9.
Strioga M, Viswanathan S, Darinskas A, Slaby O and Michalek J. (2012). Same or not the same? Comparison of adipose tissue-derived versus bone marrow-derived mesenchymal stem and stromal cells. Stem Cells Dev 21:2724–2752.
10.
Burgos-Silva M, Semedo-Kuriki P, Donizetti-Oliveira C, Costa PB, Cenedeze MA, Hiyane MI, Pacheco-Silva A and Camara NO. (2015). Adipose tissue-derived stem cells reduce acute and chronic kidney damage in mice. PLoS One 10:e0142183.
11.
Iglesias P and Diez JJ. (2010). Adipose tissue in renal disease: clinical significance and prognostic implications. Nephrol Dial Transplant 25:2066–2077.
12.
Villanueva S, Carreno JE, Salazar L, Vergara C, Strodthoff R, Fajre F, Cespedes C, Saez PJ, Irarrazabal C, et al. (2013). Human mesenchymal stem cells derived from adipose tissue reduce functional and tissue damage in a rat model of chronic renal failure. Clin Sci (Lond) 125:199–210.
13.
Villanueva S, Ewertz E, Carrion F, Tapia A, Vergara C, Cespedes C, Saez PJ, Luz P, Irarrazabal C, et al. (2011). Mesenchymal stem cell injection ameliorates chronic renal failure in a rat model. Clin Sci (Lond) 121:489–499.
14.
Klinkhammer BM, Kramann R, Mallau M, Makowska A, van Roeyen CR, Rong S, Buecher EB, Boor P, Kovacova K, et al. (2014). Mesenchymal stem cells from rats with chronic kidney disease exhibit premature senescence and loss of regenerative potential. PLoS One 9:e92115.
15.
Roemeling-van Rhijn M, Reinders ME, de Klein A, Douben H, Korevaar SS, Mensah FK, Dor FJ, IJzermans JN, Betjes MG, et al. (2012). Mesenchymal stem cells derived from adipose tissue are not affected by renal disease. Kidney Int 82:748–758.
16.
Yamanaka S, Yokote S, Yamada A, Katsuoka Y, Izuhara L, Shimada Y, Omura N, Okano HJ, Ohki T and Yokoo T. (2014). Adipose tissue-derived mesenchymal stem cells in long-term dialysis patients display downregulation of PCAF expression and poor angiogenesis activation. PLoS One 9:e102311.
17.
Hong WX, Hu MS, Esquivel M, Liang GY, Rennert RC, McArdle A, Paik KJ, Duscher D, Gurtner GC, Lorenz HP and Longaker MT. (2014). The role of hypoxia-inducible factor in wound healing. Adv Wound Care (New Rochelle) 3:390–399.
18.
Huang LE, Gu J, Schau M and Bunn HF. (1998). Regulation of hypoxia-inducible factor 1[alpha] is mediated by an O2-dependent degradation domain via the ubiquitin-proteasome pathway. Proc Natl Acad Sci U S A 95:7987–7992.
19.
Noh H, Yu MR, Kim HJ, Jang EJ, Hwang ES, Jeon JS, Kwon SH and Han DC. (2014). Uremic toxin p-cresol induces Akt-pathway-selective insulin resistance in bone marrow-derived mesenchymal stem cells. Stem Cells 32:2443–2453.
20.
Noh H, Yu MR, Kim HJ, Jeon JS, Kwon SH, Jin SY, Lee J, Jang J, Park JO, et al. (2012). Uremia induces functional incompetence of bone marrow-derived stromal cells. Nephrol Dial Transplant 27:218–225.
21.
Callapina M, Zhou J, Schmid T, Kohl R and Brune B. (2005). NO restores HIF-1alpha hydroxylation during hypoxia: role of reactive oxygen species. Free Radic Biol Med 39:925–936.
22.
Movafagh S, Crook S and Vo K. (2015). Regulation of hypoxia-inducible factor-1a by reactive oxygen species: new developments in an old debate. J Cell Biochem 116:696–703.
23.
Qutub AA and Popel AS. (2008). Reactive oxygen species regulate hypoxia-inducible factor 1alpha differentially in cancer and ischemia. Mol Cell Biol 28:5106–5119.
24.
Oberg BP, McMenamin E, Lucas FL, McMonagle E, Morrow J, Ikizler TA and Himmelfarb J. (2004). Increased prevalence of oxidant stress and inflammation in patients with moderate to severe chronic kidney disease. Kidney Int 65:1009–1016.
25.
Tepel M, Echelmeyer M, Orie NN and Zidek W. (2000). Increased intracellular reactive oxygen species in patients with end-stage renal failure: effect of hemodialysis. Kidney Int 58:867–872.
26.
Kimura K, Nagano M, Salazar G, Yamashita T, Tsuboi I, Mishima H, Matsushita S, Sato F, Yamagata K and Ohneda O. (2014). The role of CCL5 in the ability of adipose tissue-derived mesenchymal stem cells to support repair of ischemic regions. Stem Cells Dev 23:488–501.
27.
Ceradini DJ, Kulkarni AR, Callaghan MJ, Tepper OM, Bastidas N, Kleinman ME, Capla JM, Galiano RD, Levine JP and Gurtner GC. (2004). Progenitor cell trafficking is regulated by hypoxic gradients through HIF-1 induction of SDF-1. Nat Med 10:858–864.
28.
Schmidt S, Westhoff TH, Krauser P, Zidek W and van der Giet M. (2008). The uraemic toxin phenylacetic acid increases the formation of reactive oxygen species in vascular smooth muscle cells. Nephrol Dial Transplant 23:65–71.
29.
Watanabe H, Miyamoto Y, Enoki Y, Ishima Y, Kadowaki D, Kotani S, Nakajima M, Tanaka M, Matsushita K, et al. (2015). p-Cresyl sulfate, a uremic toxin, causes vascular endothelial and smooth muscle cell damages by inducing oxidative stress. Pharmacol Res Perspect 3:e00092.
30.
Valle-Prieto A and Conget PA. (2010). Human mesenchymal stem cells efficiently manage oxidative stress. Stem Cells Dev 19:1885–1893.
31.
Lee EY, Xia Y, Kim W, Kim MH, Kim TH and Kim KJ. (2009). Hypoxia-enhanced wound-healing function of adipose-derived stem cells: increase in stem cell proliferation and up-regulation of VEGF and bFGF. Wound Repair Regen 17:540–547.
32.
Nagano M, Yamashita T, Hamada H, Ohneda K, Kimura K, Nakagawa T, Shibuya M, Yoshikawa H and Ohneda O. (2007). Identification of functional endothelial progenitor cells suitable for the treatment of ischemic tissue using human umbilical cord blood. Blood 110:151–160.
33.
Trinh NT, Yamashita T, Ohneda K, Kimura K, Salazar GT, Sato F and Ohneda O. (2016). Increased expression of EGR-1 in diabetic human adipose tissue-derived mesenchymal stem cells reduces their wound healing capacity. Stem Cells Dev 25:760–773.
34.
Huang S-Y, Chen Y-A, Chen S-A, Chen Y-J and Lin Y-K. (2016). Uremic toxins—novel arrhythmogenic factor in chronic kidney disease-related atrial fibrillation. Acta Cardiol Sin 32:259–264.
35.
Lisowska-Myjak B. (2014). Uremic toxins and their effects on multiple organ systems. Nephron Clin Pract 128:303–311.
36.
Schioppa T, Uranchimeg B, Saccani A, Biswas SK, Doni A, Rapisarda A, Bernasconi S, Saccani S, Nebuloni M, et al. (2003). Regulation of the chemokine receptor CXCR4 by hypoxia. J Exp Med 198:1391–1402.
37.
Schofield CJ and Ratcliffe PJ. (2004). Oxygen sensing by HIF hydroxylases. Nat Rev Mol Cell Biol 5:343–354.
38.
Metzen E, Berchner-Pfannschmidt U, Stengel P, Marxsen JH, Stolze I, Klinger M, Huang WQ, Wotzlaw C, Hellwig-Burgel T, et al. (2003). Intracellular localisation of human HIF-1 alpha hydroxylases: implications for oxygen sensing. J Cell Sci 116:1319–1326.
39.
Ito S and Yoshida M. (2014). Protein-bound uremic toxins: new culprits of cardiovascular events in chronic kidney disease patients. Toxins 6:665–678.
40.
Song H, Cha M-J, Song B-W, Kim I-K, Chang W, Lim S, Choi EJ, Ham O, Lee S-Y, et al. (2010). Reactive oxygen species inhibit adhesion of mesenchymal stem cells implanted into ischemic myocardium via interference of focal adhesion complex. Stem Cells 28:555–563.
41.
Hellfritsch J, Kirsch J, Schneider M, Fluege T, Wortmann M, Frijhoff J, Dagnell M, Fey T, Esposito I, et al. (2015). Knockout of mitochondrial thioredoxin reductase stabilizes prolyl hydroxylase 2 and inhibits tumor growth and tumor-derived angiogenesis. Antioxid Redox Signal 22:938–950.
42.
Han WQ, Zhu Q, Hu J, Li PL, Zhang F and Li N. (2013). Hypoxia-inducible factor prolyl-hydroxylase-2 mediates transforming growth factor beta 1-induced epithelial-mesenchymal transition in renal tubular cells. Biochim Biophys Acta 1833:1454–1462.
43.
McMahon S, Charbonneau M, Grandmont S, Richard DE and Dubois CM. (2006). Transforming growth factor beta1 induces hypoxia-inducible factor-1 stabilization through selective inhibition of PHD2 expression. J Biol Chem 281:24171–24181.
44.
Berra E, Benizri E, Ginouvès A, Volmat V, Roux D and Pouysségur J. (2003). HIF prolyl-hydroxylase 2 is the key oxygen sensor setting low steady-state levels of HIF-1α in normoxia. EMBO J 22:4082–4090.
45.
Niecknig H, Tug S, Reyes BD, Kirsch M, Fandrey J and Berchner-Pfannschmidt U. (2012). Role of reactive oxygen species in the regulation of HIF-1 by prolyl hydroxylase 2 under mild hypoxia. Free Radic Res 46:705–717.
46.
Fong GH and Takeda K. (2008). Role and regulation of prolyl hydroxylase domain proteins. Cell Death Differ 15:635–641.
47.
Burr Stephen P, Costa ASH, Grice GL, Timms RT, Lobb IT, Freisinger P, Dodd RB, Dougan G, Lehner PJ, Frezza C and Nathan JA. Mitochondrial protein lipoylation and the 2-oxoglutarate dehydrogenase complex controls HIF1α stability in aerobic conditions. Cell Metab 24:740–752.

Information & Authors

Information

Published In

cover image Stem Cells and Development
Stem Cells and Development
Volume 26Issue Number 13July 1, 2017
Pages: 948 - 963
PubMed: 28537846

History

Published in print: July 1, 2017
Published online: 1 July 2017
Published ahead of print: 24 May 2017
Accepted: 14 April 2017
Received: 16 November 2016

Permissions

Request permissions for this article.

Topics

Authors

Affiliations

Vuong Cat Khanh
Graduate School of Comprehensive Human Science, Laboratory of Regenerative Medicine and Stem Cell Biology, University of Tsukuba, Tsukuba, Japan.
Kinuko Ohneda
Takasaki University of Health and Welfare Laboratory of Molecular Pathophysiology, Takasaki, Japan.
Toshiki Kato
Graduate School of Comprehensive Human Science, Laboratory of Regenerative Medicine and Stem Cell Biology, University of Tsukuba, Tsukuba, Japan.
Toshiharu Yamashita
Graduate School of Comprehensive Human Science, Laboratory of Regenerative Medicine and Stem Cell Biology, University of Tsukuba, Tsukuba, Japan.
Fujio Sato
Department of Cardiovascular Surgery, University of Tsukuba, Tsukuba, Japan.
Kana Tachi
Department of Breast-Thyroid-Endocrine Surgery, University of Tsukuba, Tsukuba, Japan.
Osamu Ohneda
Graduate School of Comprehensive Human Science, Laboratory of Regenerative Medicine and Stem Cell Biology, University of Tsukuba, Tsukuba, Japan.

Notes

Address correspondence to:Prof. Osamu OhnedaGraduate School of Comprehensive Human ScienceLaboratory of Regenerative Medicine and Stem Cell BiologyUniversity of Tsukuba1-1-1 TennoudaiTsukuba 305-8575Japan
E-mail: [email protected]

Author Disclosure Statement

No competing financial interests exist.

Metrics & Citations

Metrics

Citations

Export citation

Select the format you want to export the citations of this publication.

View Options

Get Access

Access content

To read the fulltext, please use one of the options below to sign in or purchase access.

Society Access

If you are a member of a society that has access to this content please log in via your society website and then return to this publication.

Restore your content access

Enter your email address to restore your content access:

Note: This functionality works only for purchases done as a guest. If you already have an account, log in to access the content to which you are entitled.

View options

PDF/EPUB

View PDF/ePub

Full Text

View Full Text

Media

Figures

Other

Tables

Share

Share

Copy the content Link

Share on social media

Back to Top