Renal Regeneration in proteinuric CKD

Abstract

Recent progress in kidney regeneration includes the directed differentiation ofembryonic stem cells to kidney fates, understanding the proliferative capacity oftubules after injury, the use of mesenchymal stem cells for kidney disease and therole of the glomerular parietal epithelial cell. Glomerular diseases characterizedby chronic proteinuria are the leading causes of chronic and end-stage kidneydisease. Proteinuria contributes directly to progressive glomerulosclerosis throughthe suppression of podocyte regeneration and individual components of proteinu-ria exert distinct effects on renal progenitor survival and differentiation toward apodocyte lineage. In particular, albumin prevented podocyte differentiation fromhuman renal progenitors in vitro by sequestering retinoic acid, thus impairingretinoic acid response element-mediated transcription of podocyte-specific genes.In mice with adriamycin nephropathy, a model of human FSGS, blockingendogenous retinoic acid synthesis increased proteinuria and exacerbatedglomerulosclerosis.While mesenchymal stem cells have demonstrated potential for the preventionof acute kidney injury, little is known of its role in chronic kidney disease.Glomerular diseases characterized by chronic proteinuria are the leading causes ofchronic and end-stage kidney disease. Renal prognosis in CKD is largely deter-mined by the degree of renal tubular injury that correlates with residual albumi-nuria. Using a co-culture model of human proximal tubular epithelial cells(PTECs) and BM-MSCs, we showed that concomitant stimulation of BM-MSCsby albumin excess was a prerequisite for them to attenuate albumin-induced IL-6,IL-8, TNF-α, CCL-2, CCL-5 expression and epithelial-to-mesenchymal transi-tion (EMT) in PTECs, which was partly mediated via deactivation of tubularNF-κB signaling. Albumin-overloaded BM-MSCs per se overexpressedhepatocyte growth factor (HGF) and TNFα-stimulating gene (TSG)-6 viaP38 and NF-κB signaling. These paracrine factors suppressed both theproinflammatory and profibrotic phenotypes in albumin-induced PTECs. Neu-tralizing HGF and TSG-6 abolished the anti-inflammatory and anti-EMT effectsof BM-MSC co-culture in albumin-induced PTECs, respectively. Albumin-overloaded mice treated with mouse BM-MSCs had markedly reduced BUN,tubular CCL-2 and CCL-5 expression, interstitial macrophage, α-SMA and col-lagen IV accumulation independent of changes in proteinuria, with upregulatedrenal cortical HGF expression. Exogenous BM-MSCs were detected in theirkidneys. These data suggest a modulatory effect of BM-MSCs on albumin-induced tubular inflammation and fibrosis and underscore a therapeutic potentialof BM-MSCs in proteinuric CKD.