title: Mesenchymal stem cells modulate albumin-induced renal tubular inflammation and fibrosis.
abstract: Bone marrow-derived mesenchymal stem cells (BM-MSCs) have recently shown promise as a therapeutic tool in various types of chronic kidney disease (CKD) models. However, the mechanism of action is incompletely understood. As renal prognosis in CKD is largely determined by the degree of renal tubular injury that correlates with residual proteinuria, we hypothesized that BM-MSCs may exert modulatory effects on renal tubular inflammation and epithelial-to-mesenchymal transition (EMT) under a protein-overloaded milieu. Using a co-culture model of human proximal tubular epithelial cells (PTECs) and BM-MSCs, we showed that concomitant stimulation of BM-MSCs by albumin excess was a prerequisite for them to attenuate albumin-induced IL-6, IL-8, TNF-α, CCL-2, CCL-5 overexpression in PTECs, which was partly mediated via deactivation of tubular NF-κB signaling. In addition, albumin induced tubular EMT, as shown by E-cadherin loss and α-SMA, FN and collagen IV overexpression, was also prevented by BM-MSC co-culture. Albumin-overloaded BM-MSCs per se retained their tri-lineage differentiation capacity and overexpressed hepatocyte growth factor (HGF) and TNFα-stimulating gene (TSG)-6 via P38 and NF-κB signaling. Albumin-induced tubular CCL-2, CCL-5 and TNF-α overexpression were suppressed by recombinant HGF treatment, while the upregulation of α-SMA, FN and collagen IV was attenuated by recombinant TSG-6. Neutralizing HGF and TSG-6 abolished the anti-inflammatory and anti-EMT effects of BM-MSC co-culture in albumin-induced PTECs, respectively. In vivo, albumin-overloaded mice treated with mouse BM-MSCs had markedly reduced BUN, tubular CCL-2 and CCL-5 expression, α-SMA and collagen IV accumulation independent of changes in proteinuria. These data suggest anti-inflammatory and anti-fibrotic roles of BM-MSCs on renal tubular cells under a protein overloaded condition, probably mediated via the paracrine action of HGF and TSG-6.
authors.affiliation: Nephrology Division, The University of Hong Kong, Queen Mary Hospital, Hong Kong.
authors.forename: Hao Jia
authors.initials: HJ
authors.lastname: Wu
authors.affiliation: Nephrology Division, The University of Hong Kong, Queen Mary Hospital, Hong Kong.
authors.forename: Wai Han
authors.initials: WH
authors.lastname: Yiu
authors.affiliation: Nephrology Division, The University of Hong Kong, Queen Mary Hospital, Hong Kong.
authors.forename: Rui Xi
authors.initials: RX
authors.lastname: Li
authors.affiliation: Nephrology Division, The University of Hong Kong, Queen Mary Hospital, Hong Kong.
authors.forename: Dickson W L
authors.initials: DW
authors.lastname: Wong
authors.affiliation: Nephrology Division, The University of Hong Kong, Queen Mary Hospital, Hong Kong.
authors.forename: Joseph C K
authors.initials: JC
authors.lastname: Leung
authors.affiliation: Nephrology Division, The University of Hong Kong, Queen Mary Hospital, Hong Kong.
authors.forename: Loretta Y Y
authors.initials: LY
authors.lastname: Chan
authors.affiliation: Cardiology Division, Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong.
authors.forename: Yuelin
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Cardiology Division, Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong; Department of Ophthalmology, The University of Hong Kong, Queen Mary Hospital, Hong Kong.
authors.forename: Qizhou
authors.initials: Q
authors.lastname: Lian
authors.affiliation: Nephrology Division, The University of Hong Kong, Queen Mary Hospital, Hong Kong.
authors.forename: Miao
authors.initials: M
authors.lastname: Lin
authors.affiliation: Cardiology Division, Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong.
authors.forename: Hung Fat
authors.initials: HF
authors.lastname: Tse
authors.affiliation: Nephrology Division, The University of Hong Kong, Queen Mary Hospital, Hong Kong.
authors.forename: Kar Neng
authors.initials: KN
authors.lastname: Lai
authors.affiliation: Nephrology Division, The University of Hong Kong, Queen Mary Hospital, Hong Kong.
authors.forename: Sydney C W
authors.initials: SC
authors.lastname: Tang
mesh_terms: D000199:Actins / Q000235:genetics / Q000378:metabolism; D000418:Albumins / Q000494:pharmacology*; D001854:Bone Marrow Cells / Q000166:cytology* / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D018946:Chemokine CCL5 / Q000235:genetics / Q000378:metabolism; D018920:Coculture Techniques; D024141:Collagen Type IV / Q000235:genetics / Q000378:metabolism; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D005355:Fibrosis / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D005786:Gene Expression Regulation; D017228:Hepatocyte Growth Factor / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D061251:Primary Cell Culture; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: C541116:ACTA2 protein, human; D000199:Actins; D000418:Albumins; C111835:CCL2 protein, human; C483024:CCL5 protein, human; D015815:Cell Adhesion Molecules; D018932:Chemokine CCL2; D018946:Chemokine CCL5; D024141:Collagen Type IV; C066855:HGF protein, human; C508600:IL6 protein, human; D015850:Interleukin-6; D016209:Interleukin-8; D016328:NF-kappa B; C072273:TNFAIP6 protein, human; D014409:Tumor Necrosis Factor-alpha; D017228:Hepatocyte Growth Factor