Abstract
BackgroundTubulointerstitial fibrosis (TIF) is one of the main pathological features of various progressive renal damages and chronic kidney diseases. Mesenchymal stromal cells (MSCs) have been verified with significant improvement in the therapy of fibrosis diseases, but the mechanism is still unclear. We attempted to explore the new mechanism and therapeutic target of MSCs against renal fibrosis based on renal proteomics.MethodsTIF model was induced by adenine gavage. Bone marrow-derived MSCs was injected by tail vein after modeling. Renal function and fibrosis related parameters were assessed by Masson, Sirius red, immunohistochemistry, and western blot. Renal proteomics was analyzed using iTRAQ-based mass spectrometry. Further possible mechanism was explored by transfected galectin-3 gene for knockdown (Gal-3 KD) and overexpression (Gal-3 OE) in HK-2 cells with lentiviral vector.ResultsMSCs treatment clearly decreased the expression of α-SMA, collagen type I, II, III, TGF-β1, Kim-1, p-Smad2/3, IL-6, IL-1β, and TNFα compared with model rats, while p38 MAPK increased. Proteomics showed that only 40 proteins exhibited significant differences (30 upregulated, 10 downregulated) compared MSCs group with the model group. Galectin-3 was downregulated significantly in renal tissues and TGF-β1-induced rat tubular epithelial cells and interstitial fibroblasts, consistent with the iTRAQ results. Gal-3 KD notably inhibited the expression of p-Akt, p-GSK3β and snail in TGF-β1-induced HK-2 cells fibrosis. On the contrary, Gal-3 OE obviously increased the expression of p-Akt, p-GSK3β and snail.ConclusionThe mechanism of MSCs anti-renal fibrosis was probably mediated by galectin-3/Akt/GSK3β/Snail signaling pathway. Galectin-3 may be a valuable target for treating renal fibrosis.
Highlights
Adenine-induced nephropathy is a rat model of human tubulointerstitial fibrosis (TIF), which is the main pathological feature of various progressive renal damage and the final common pathway for chronic kidney disease (CKD)
Mesenchymal stromal cells (MSCs) ameliorated renal function in adenine-induced nephropathy We examined the therapeutic effects of MSCs on renal injury in adenine-treated rats
Adenine was carried out intragastric administration continuously for 20 days, and MSCs were transplanted on day 3, and creatinine, urea nitrogen, and 24 h urinary protein were analyzed on days 0, 20, and 30
Summary
Adenine-induced nephropathy is a rat model of human tubulointerstitial fibrosis (TIF), which is the main pathological feature of various progressive renal damage and the final common pathway for chronic kidney disease (CKD). Adenine is mainly used to participate in the synthesis of DNA and RNA and has been widely used for the treatment of patients with leukopenia [2]. It causes severe nephrotoxicity and fibrosis because of the high accumulation in the kidney. Tubulointerstitial fibrosis (TIF) is one of the main pathological features of various progressive renal damages and chronic kidney diseases. We attempted to explore the new mechanism and therapeutic target of MSCs against renal fibrosis based on renal proteomics
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