Thymosin β4 alleviates renal fibrosis and tubular cell apoptosis through TGF-β pathway inhibition in UUO rat models

Abstract

BackgroundThymosin β4 (Tβ4) is closely associated with the cytoskeleton, inflammation, wound healing, angiogenesis, apoptosis, and myocardial regeneration, but the effects of Tβ4 treatment on chronic renal tubular interstitial fibrosis (CRTIF) are poorly known. This study aimed to examine the effects of Tβ4 on the renal apoptosis and the expression of transforming growth factor (TGF-β), E-cadherin, and α-smooth muscle actin (α-SMA) in CRTIF rat models.MethodsMale SD rats were randomized into four groups (sham group, unilateral ureteral obstruction (UUO) group, UUO + low-dose Tβ4 group, and UUO + high-dose Tβ4 group). The pathological changes of kidney tissue and its function were assessed two weeks after UUO. In renal interstitial tissue,TGF-β, E-cadherin and α-SMA expression was detected by western blot. In tubular epithelial cells, E-cadherin and α-SMA expression was detected using Real-time qPCR and western blot. Cell apoptosis of rat renal interstitial tissue and tubular epithelial cells was evaluated by immunofluorescence and western blot.ResultsTwo weeks after UUO, no differences in blood urea nitrogen and creatinine were observed between the four groups (P > 0.05). Compared to the UUO group, Tβ4 treatment decreased the 24-h proteinuria (P < 0.001) and reduced the area of pathological change (P < 0.01); this effect was more apparent in the UUO + high-dose Tβ4 group. Compared to the UUO group, a significant decrease in TGF-β and α-SMA protein expression was observed in the high-dose Tβ4 group. The level of E-cadherin protein was lower in the UUO group than the Tβ4 groups, and high-dose Tβ4 treatment further increased E-cadherin expression and improved cell apoptosis in the renal interstitial tissue. Analysis of in vitro tubular epithelial cells showed that α-SMA mRNA and protein expression decreased, while E-cadherin mRNA and protein expression increased by Tβ4 treatment. Similarly, these changes were more significant in the UUO + high-dose Tβ4 group. Tβ4 treatment improved the apoptosis of In vitro tubular epithelial cells compared with pure TGF-β stimulation, and equally, the decrease of apoptosis was more apparent in the TGF-β + high-dose Tβ4 group.ConclusionsTβ4 treatment might alleviate the renal fibrosis and apoptosis of tubular epithelial cells through TGF-β pathway inhibition in UUO rats with CRTIF.Electronic supplementary materialThe online version of this article (10.1186/s12882-017-0708-1) contains supplementary material, which is available to authorized users.

Long noncoding RNA growth arrest‐specific transcript 5 alleviates renal fibrosis in diabetic nephropathy by downregulating matrix metalloproteinase 9 through recruitment of enhancer of zeste homolog 2

“…Also, TGF-β can induce the activation of α-SMA in fibroblast cells, which facilitates the shrinkage of fibrotic tissues, thus leading to ischemia and hypoxia of renal tissues. 36 Besides, the activation of TGF-β1 is indicative of the occurrence of DN, and therefore, the suppressed expression of TGF-β1 and α-SMA may alleviate renal fibrosis. [37][38][39] Myofibroblast marker α-SMA can be reduced by increased expression of GAS5-AS1 to against renal fibrosis formation.…”

A self‐organized actomyosin drives multiple intercellular junction disruption and directly promotes neutrophil recruitment in lipopolysaccharide‐induced acute lung injury

“…4. LPS + S + BLEB or LatA or Y27632 or ML-7 or Tb4 groups: media were replaced with neutrophil supernatants 5 h after LPS treatment, cells were treated with LPS, and BLEB (10 mM) (26), LatA (1 mM) (27), Y27632 (10 mM) (26), ML-7 (10 mM) (28), or Tb4 protein (1 mg/ml) (29) was added, respectively. 5.…”

Thymosin-β4: A key modifier of renal disease

“…These effects were particularly pronounced in the high dose thymosin-b4 group compared with the UUO group administered saline. 50 Overall, these studies provide evidence for an anti-fibrotic effect of thymosin-b4 in renal interstitial fibrosis through inhibition of TGF-β signalling.…”

“…35 Another study demonstrated a beneficial effect of exogenous thymosin-b4 in the rat UUO model. 50 Adult Sprague Dawley male rats underwent UUO or sham surgery and were subsequently treated daily with 1 or 5 mg/kg thymosin-b4 or saline administered by intragastric lavage. Treatment with thymosin-b4, was shown to alleviate fibrosis assessed by light microscopy, reduce TGF-β and aSMA upregulation, restore E-Cadherin protein levels and reduce apoptosis of renal tubular cells.…”