Objectives: 

Tubulointerstitial fibrosis, one of the common end points of chronic renal insufficiency, is characterized by an excessive accumulation of extracellular matrix (ECM) in the renal interstitium, myofibroblast activation, cell infiltration, tubular apoptosis and proliferation. Transforming growth factor-beta 1 (TGFbeta1) is considered a fundamental profibrotic cytokine that transduces signals through ALK5/Smad2/3 and ALK1/Smad1/5 pathways. ALK1 (activin receptor-like kinase I) is a type I receptor for TGFbeta1 with a pivotal role in endothelial proliferation and migration. Nevertheless, the role of ALK1 in obstructive nephropathy is unknown.

Materials: 

We performed unilateral ureteral obstruction (UUO), an obstructive nephropathy experimental model, in haploinsufficient (ALK1+/­) and control (ALK1+/+) mice in order to analyze the role of ALK1 15 days following UUO. We analyzed ECM proteins, proliferation and myofibroblasts markers and Smads phosphorylation by western-blot and immunohistochemistry.

Results: 

There is an increase in ECM protein expression in obstructed kidneys from ALK1+/+ and ALK1+/­ mice, but obstructed kidneys from ALK1+/­ mice show significantly higher expressions of type I collagen and fibronectin than obstructed kidneys from ALK1+/+ mice. PCNA and Ki67 are increased 15 days following UUO in obstructed kidneys from ALK1+/+ and ALK1+/­ mice, but this increase is significantly higher in ALK1+/­ kidneys than in ALK1+/+ kidneys. There is also an increase in myofibroblasts markers (alpha-sma and S100A4) following UUO, without any difference between obstructed kidneys from ALK1+/+ and ALK1+/­ mice. Phospho-Smad1 and Phospho-Smad3 expressions are increased following UUO in both ALK1+/+ and ALK1+/­ obstructed kidneys. Phospho-Smad1 expression is lower, while Phospho-Smad3 is higher in obstructed kidneys from ALK1+/­ mice than in wild type mice.

Conclusions: 

Our data suggest a relevant role of the ALK1 receptor in the development of renal fibrosis, due to a regulation of Smad signalling.