Abstract
Tubulointerstitial injuries are known to predict the deterioration of renal function in chronic kidney disease (CKD). We recently reported the protective role of Vasohibin‐1(VASH‐1), a negative feedback regulator of angiogenesis, in diabetic nephropathy, but its impact on tubulointerstitial injuries remains to be elucidated. In the present study, we evaluated the role of endogenous VASH‐1 in regulating the tubulointerstitial alterations induced by unilateral ureteral obstruction (UUO), and assessed its role on fibrogenesis and the activation of Smad3 signaling in renal fibroblasts. UUO was induced in female Vasohibin‐1 heterozygous knockout mice (VASH‐1+/−) or wild‐type (WT) (VASH‐1+/+) littermates. Mice were sacrificed on Day 7 after left ureter ligation, and the kidney tissue was obtained. Interstitial fibrosis, the accumulation of type I and type III collagen and monocytes/macrophages infiltration in the obstructed kidneys (OBK) were significantly exacerbated in VASH‐1+/− mice compared with WT mice (Day 7). The increases in the renal levels of TGF‐β1, pSmad3, NF‐κB pp65, CCL2 mRNA, and the number of interstitial fibroblast‐specific protein‐1 (FSP‐1)+ fibroblasts in the OBK were significantly aggravated in VASH‐1+/− mice. In addition, treatment with VASH‐1 siRNA enhanced the TGF‐β1‐induced phosphorylation of Smad3, the transcriptional activation of the Smad3 pathway and the production of type I/type III collagen in fibroblasts, in vitro. Taken together, our findings demonstrate a protective role for endogenous VASH‐1 on tubulointerstitial alterations via its regulation of inflammation and fibrosis and also show the direct anti‐fibrotic effects of VASH‐1 on renal fibroblasts through its modulation of TGF‐β1 signaling.
Highlights
Tubulointerstitial alterations are characteristic histological features involved in the progression of chronic kidney disease (CKD)
The induction of ureteral obstruction (UUO) is followed by inflammatory cell infiltration, proliferation, and apoptosis of tubular epithelial cells, tubular atrophy and the accumulation of fibroblasts, resulting in interstitial fibrosis (Bascands and Schanstra 2005)
We previously reported the therapeutic effects of VASH-1 overexpression in two mouse models of diabetic nephropathy (Nasu et al 2009; Saito et al 2011)
Summary
Tubulointerstitial alterations are characteristic histological features involved in the progression of chronic kidney disease (CKD). These alterations include the interstitial infiltration of monocytes/macrophages, accumulation of myofibroblasts, proliferation of interstitial fibroblasts and accumulation of extracellular matrix (ECM) proteins, resulting in interstitial fibrosis (Eddy 1996). Myofibroblasts play an important role in the process of kidney fibrosis, including that occurring during UUO, but the origin of the myofibroblasts associated with renal interstitial fibrosis has been debated. The proliferation of residential tissue fibroblasts, the differentiation of bone marrow-derived mesenchymal stem cells, tubular epithelial cells, vascular pericytes of the peritubular capillaries (PTC; Lin et al 2011) and endothelial cells are the postulated origins of the renal myofibroblasts (LeBleu et al 2013)
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