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.

Management of Fibrosis: The Mesenchymal Stromal Cells Breakthrough

“…In addition to suppressing the secretion of TNF- α by activated macrophages, this protein induces a change in the TGF- β 1/TGF- β 3 balance, from a profibrotic high ratio to an antifibrotic low ratio [77]. These results are confirmed in a coculture model in which recombinant TSG-6 partially reproduced the effects of MSCs [62]. …”

Renoprotective effects of angiotensin receptor blocker and stem cells in acute kidney injury: Involvement of inflammatory and apoptotic markers

“…32 The antiinflammatory and antifibrotic activities of BM-MSCs were indicated by attenuation of the TNF-a and NF-jB overexpression in a recent model of albumininduced renal tubular inflammation and fibrosis. 37 The MSCs have a prominent immunomodulatory property that leads to the downregulation of inflammatory reactions. 38 Moreover, BM-MSCs also significantly suppressed the renal p38-MAPK, caspase-3 and Bax expressions in CDDP-treated rats.…”

Recent Progress in Stem Cell Therapy for Diabetic Nephropathy

“…Hence, engrafted MSCs might modify the injured kidney by secreting these factors to trigger intracellular signaling in target cells or neighboring cells. We demonstrated that bone marrow MSCs modulate albumin-induced renal tubular inflammation and fibrosis by secreting hepatocyte growth factor and TNF-stimulated gene 6 (TSG-6) both in vitro and in vivo [70] . Conditioned medium of human umbilical cord blood-derived MSCs significantly inhibited α-SMA, TGF-β 1 , collagen I, and Hsp 47 upregulation and E-cadherin and BMP-7 downregulation induced by TGF-β 1 in NRK-52E cells in a dose-dependent manner through secretion of humoral factors [71] .…”