Tubulointerstitial fibrosis (TIF) is a prominent factor in the progression of chronic kidney disease (CKD) regardless of etiology. ErbB4 expression levels were inversely correlated to renal fibrosis in human fibrotic kidneys. In both unilateral ureteral obstruction (UUO) and ischemia reperfusion injury followed by uninephrectomy (IRI/UNx) mouse models, expression levels of ErbB4 were elevated in the early stage of renal injury. Using mice with global ErbB4 deletion except for transgenic rescue in cardiac tissue (ErbB4-/-ht+), we determined that UUO induced similar injury in proximal tubules compared to wild-type mice but more severe injury in distal nephrons. TIF was apparent earlier and was more pronounced following UUO in ErbB4-/-ht+ mice. With ErbB4 deletion, UUO injury inhibited AKT phosphorylation and increased the percentage of cells in G2/M arrest. There was also increased nuclear immunostaining of YAP and increased expression of p-Smad3, snail1 and vimentin. These results indicate that ErbB4 deletion accelerates the development and progression of renal fibrosis in obstructive nephropathy. Similar results were found in a mouse IRI/UNx model. In conclusion, increased expression of ErbB4 in the early stages of renal injury may reflect a compensatory effect to lessen tubulointerstitial injury.