Treatment With Human Wharton's Jelly-Derived Mesenchymal Stem Cells Attenuates Sepsis-Induced Kidney Injury, Liver Injury, and Endothelial Dysfunction

The pathophysiology of sepsis involves complex cytokine and inflammatory mediator networks. Downregulation of endothelial nitric oxide synthase contributes to sepsis-induced endothelial dysfunction. Human Wharton's jelly-derived mesenchymal stem cells (WJ-MSCs) are known to reduce expression of proinflammatory cytokines and markers of apoptosis. We hypothesized that treatment with WJ-MSCs would protect renal, hepatic, and endothelial function in a cecal ligation and puncture (CLP) model of sepsis in rats. Rats were randomly divided into three groups: sham-operated rats; rats submitted to CLP and left untreated; and rats submitted to CLP and intraperitoneally injected, 6 hours later, with 1 x 10(6) WJ-MSCs. The glomerular filtration rate (GFR) was measured at 6 and 24 hours after CLP or sham surgery. All other studies were conducted at 24 hours after CLP or sham surgery. By 6 hours, GFR had decreased in the CLP rats. At 24 hours, Klotho renal expression significantly decreased. Treatment with WJ-MSCs improved the GFR; improved tubular function; decreased the CD68-positive cell count; decreased the fractional interstitial area; decreased expression of nuclear factor kappa B and of cytokines; increased expression of eNOS, vascular endothelial growth factor, and Klotho; attenuated renal apoptosis; ameliorated hepatic function; increased glycogen deposition in the liver; and improved survival. Sepsis-induced acute kidney injury is a state of Klotho deficiency, which WJ-MSCs can attenuate. Klotho protein expression was higher in WJ-MSCs than in human adipose-derived MSCs. Because WJ-MSCs preserve renal and hepatic function, they might play a protective role in sepsis. SIGNIFICANCE Sepsis is the leading cause of death in intensive care units. Although many different treatments for sepsis have been tested, sepsis-related mortality rates remain high. It was hypothesized in this study that treatment with human Wharton's jelly-derived mesenchymal stem cells (WJ-MSCs) would protect renal, hepatic, and endothelial function in a model of sepsis in rats. Treatment with WJ-MSCs improved the glomerular filtration rate, improved tubular function, decreased expression of nuclear factor kappa B and of cytokines, increased expression of eNOS and of Klotho, attenuated renal apoptosis, and improved survival. Sepsis-induced acute kidney injury is a state of Klotho deficiency, which WJ-MSCs can attenuate.

Palavras-chave

Wharton's jelly-derived mesenchymal stem cells, Kidney injury, Liver injury, Endothelium-derived factors, Apoptosis, Interleukins

URI

https://observatorio.fm.usp.br/handle/OPI/17001

Referências

Abraham E, 2007, CRIT CARE MED, V35, P2408, DOI 10.1097/01.CCM.0000282072.56245.91
Aggarwal S, 2005, BLOOD, V105, P1815, DOI 10.1182/blood-2004-04-1559
Bagshaw SM, 2007, CLIN J AM SOC NEPHRO, V2, P431, DOI 10.2215/CJN.03681106
Chang CL, 2012, J TRANSL MED, V10, DOI 10.1186/1479-5876-10-244
Dellinger RP, 2013, CRIT CARE MED, V41, P580, DOI 10.1097/CCM.0b013e31827e83af
Di Lanni M, 2008, EXP HEMATOL, V36, P309, DOI 10.1016/j.exphem.2007.11.007
Doi K, 2009, J CLIN INVEST, V119, P2868, DOI 10.1172/JCI39421
Elman JS, 2014, J INFLAMM-LOND, V11, DOI 10.1186/1476-9255-11-1
English K, 2009, CLIN EXP IMMUNOL, V156, P149, DOI 10.1111/j.1365-2249.2009.03874.x
Gonzalez-Rey E, 2009, GUT, V58, P929, DOI 10.1136/gut.2008.168534
Hotchkiss RS, 2006, NAT REV IMMUNOL, V6, P813, DOI 10.1038/nri1943
Hu MC, 2010, KIDNEY INT, V78, P1240, DOI 10.1038/ki.2010.328
Jawad Issrah, 2012, J Glob Health, V2, P010404, DOI 10.7189/jogh.02.010404
Jesmin S, 2012, INFLAMMATION, V35, P484, DOI 10.1007/s10753-011-9337-1
Jin HJ, 2013, INT J MOL SCI, V14, P17986, DOI 10.3390/ijms140917986
Jorge L, 2013, J AM SOC NEPHROL, V24
Kotsaki A, 2012, EXPERT OPIN EMERG DR, V17, P379, DOI 10.1517/14728214.2012.697151
Kusadasi N, 2013, SHOCK, V40, P352, DOI 10.1097/SHK.0000000000000039
Kyurkchiev Dobroslav, 2014, World J Stem Cells, V6, P552, DOI 10.4252/wjsc.v6.i5.552
Leelahavanichkul A, 2008, AM J PHYSIOL-RENAL, V295, pF1825, DOI 10.1152/ajprenal.90442.2008
Liu SF, 2006, AM J PHYSIOL-LUNG C, V290, pL622, DOI 10.1152/ajplung.00477.2005
Lopez A, 2004, CRIT CARE MED, V32, P21, DOI 10.1097/01.CCM.0000105581.01815.C6
Maekawa Y, 2009, ENDOCRINE, V35, P341, DOI 10.1007/s12020-009-9181-3
Mei SHJ, 2010, AM J RESP CRIT CARE, V182, P1047, DOI 10.1164/rccm.201001-0010OC
O'Sullivan AW, 2009, J SURG RES, V152, P46, DOI 10.1016/j.jss.2008.04.030
Oh HJ, 2015, PERITON DIALYSIS INT, V35, P43, DOI 10.3747/pdi.2013.00150
de Souza ACCP, 2012, AM J PHYSIOL-RENAL, V302, pF1045, DOI 10.1152/ajprenal.00148.2011
Qin SX, 2006, J EXP MED, V203, P1637, DOI 10.1084/jem.20052203
Rittirsch D, 2008, NAT REV IMMUNOL, V8, P776, DOI 10.1038/nri2402
Rochefort GY, 2006, STEM CELLS, V24, P2202, DOI 10.1634/stemcells.2006-0164
Rodrigues CE, 2012, PLOS ONE, V7, DOI 10.1371/journal.pone.0029893
Romanov YA, 2003, STEM CELLS, V21, P105, DOI 10.1634/stemcells.21-1-105
Watson N, 2015, CYTOTHERAPY, V17, P18, DOI 10.1016/j.jcyt.2014.08.009
Xu C, 2014, KIDNEY INT, V85, P72, DOI 10.1038/ki.2013.286
Xu JG, 2007, AM J PHYSIOL-LUNG C, V293, pL131, DOI 10.1152/ajplung.00431.2006
Yagi H, 2010, CELL TRANSPLANT, V19, P823, DOI 10.3727/096368910X508942
Yang HC, 2011, J AM SOC NEPHROL, V22, P2028, DOI 10.1681/ASN.2010090982
Ye XB, 2008, J EXP MED, V205, P1303, DOI 10.1084/jem.20071393
Zarbock A, 2014, CURR OPIN CRIT CARE, V20, P588, DOI 10.1097/MCC.0000000000000153
Zeldich E, 2014, J BIOL CHEM, V289, P24700, DOI 10.1074/jbc.M114.567321

Coleções

Artigos e Materiais de Revistas Científicas - FM/MCM
Artigos e Materiais de Revistas Científicas - HC/ICHC
Artigos e Materiais de Revistas Científicas - LIM/12
Artigos e Materiais de Revistas Científicas - LIM/29
Artigos e Materiais de Revistas Científicas - ODS/03

Página do item completo