Injured tubule-derived CCN1 exacerbates renal congestion-mediated acute kidney injury and fibrosis

Epidemiological studies showed that patients with heart failure frequently develop kidney dysfunction, called cardio-renal syndrome (CRS). Elevated central venous pressure rather than low cardiac output strongly correlates with worsening renal function, and is being increasingly recognized as the pathophysiology responsible for CRS. However, due to the lack of appropriate animal models, the molecular mechanisms underlying the congestion-mediated acceleration of kidney injury, called renal congestion, remain unclear. In the present study, using a novel mouse renal congestion model, we detected injured tubule-specific cell-cell interactions in congestive kidneys and showed that Cellular Communication Network Factor 1 (CCN1) played an important role in this process. Transcriptomics of kidneys with ischemia-reperfusion injury (IRI) and renal congestion revealed the up-regulation of paracrine chemokine-related pathways. The up-regulation of CCN1 was observed in the acute phase after kidney injury with renal congestion. Positive staining for phosphorylated focal adhesion kinase (pFAK), a downstream signaling molecule of CCN1, was noted in fibroblasts at injury sites in congestion-IRI kidneys. CCN1 activated the phosphorylation of FAK and ERK in vitro, which accelerated the migration of fibroblasts and macrophages. We then examined the effects of CCN1 deletion in tubular epithelia on congestion-mediated kidney injury in vivo. pFAK expression in injury sites was down-regulated in CCN1-KO mice, and the congestion-mediated worsening of tissue fibrosis was significantly ameliorated. In conclusion, we herein demonstrated the important role of injured tubule-derived CCN1 on pFAK-mediated fibroblast migration in congestive kidneys. The inhibition of CCN1 has potential as a therapeutic candidate for preventing the transition of renal congestion-mediated kidney injury to fibrosis. Overall design: RNA-seq profiling of IRI kidney with or without renal congestion at 1 day after surgery