Upregulation of HER2 in tubular epithelial cell drives fibroblast activation and renal fibrosis.

Tubular epithelial cell-derived profibrotic factors are known as the driving force in renal fibrosis for their roles in activating the surrounding fibroblast. However, the mechanisms driving their expressions remain undefined. Here, we find that kidney human epidermal growth factor receptor 2 (HER2), a member of the epidermal growth factor receptor family, significantly increased in unilateral ureteral obstruction-induced renal fibrosis, in type 1 and type 2 diabetic nephropathy, and in kidney biopsies from patients with renal fibrosis. Notably, the upregulation of HER2 mainly occurred in proximal tubular epithelial cells (PTECs). In vivo, the ectopic expression of HER2 in these cells was sufficient to activate the interstitial fibroblast and initiate interstitial fibrosis, whereas inhibiting HER2 reduced the accumulation of myofibroblasts and the extent of renal fibrosis in the mouse obstruction model and in streptozotocin (STZ)-induced diabetic mice. We also generated a tubular epithelial cell subline stably expressing HER2 and performed transcriptome RNA sequence analysis. This showed that sustained HER2 expression significantly induced the expression of profibrotic connective tissue growth factor (CTGF). Mechanistically, the induction of CTGF depended on the HER2-mediated activation of Stat3 in the tubular epithelium. In vitro, the incubation of kidney fibroblasts with culture medium from HER2-overexpressed tubular epithelial cells promoted fibroblast proliferation and activation, whereas silencing CTGF impeded the profibrotic effects of the tubular epithelial cell preconditioned media. Thus, our results highlight the significance of HER2 in tubular injury and characterize its role in promoting surrounding fibroblast activation and renal fibrosis in a paracrine manner.