Specific endothelial heparin-binding EGF-like growth factor deletion ameliorates renal injury induced by chronic angiotensin II infusion

Abstract

Transactivation of EGF receptor (EGFR) by angiotensin II (Ang II) plays important roles in the initiation and progression of chronic kidney diseases. Studies suggest that heparin-binding EGF-like factor (HB-EGF) may be a critical mediator in this process, but its role in vivo has not been investigated. In the current study, we found that in response to Ang II infusion, kidneys from endothelial HB-EGF deletion mice had significantly reduced EGFR activation compared with controls. Meanwhile, deletion of endothelial HB-EGF expression decreased Ang II infusion related renal injury, as demonstrated by 1) less albuminuria; 2) less glomerulosclerosis; 3) preserved endothelial integrity and decreased podocyte injury, as shown by greater glomerular tuft area and WT1-positive cells, and fewer apoptotic cells measured by cleaved caspase 3 staining; 4) reduced inflammation in the perivascular area and interstitium measured by F4/80 and CD3 immunostaining; and 5) reduced renal fibrosis. In conclusion, our results suggest that shedding of HB-EGF from endothelium plays an important role in Ang II-induced renal injury by linking Ang II-AT1R with EGFR transactivation. Inhibition of HB-EGF shedding could be a potential therapeutic strategy for chronic kidney disease.

iRhom2 promotes lupus nephritis through TNF-α and EGFR signaling

“…Most importantly, interstitial HB-EGF expression in human LN biopsies was associated with chronicity index, a measure of signs of irreversible kidney damage and poor prognosis. In nephrotoxic serum-induced nephritis, it is thought that HB-EGF produced from podocytes and parietal epithelial cells triggers activation of EGFR in podocytes and leads to rapidly progressive glomerulonephritis, whereas endothelium-derived HB-EGF drives angiotension II-induced renal fibrosis (13,57). Collectively, our results indicate that both renal macrophages and resident kidney cells contribute to production of HB-EGF and subsequent EGFR signaling in Fcgr2b -/-kidneys.…”

Selective activation of epidermal growth factor receptor in renal proximal tubule induces tubulointerstitial fibrosis

“…In a chronic setting, we observed a 6-fold increase of HB-EGF mRNA in hHB-EGF Tg/Tg mice and previously reported a 3-fold increase in HB-EGF protein in diabetic enos 2/2 db/db mice (33), which suggests that chronic expression as well as the expression level of the EGF family may contribute to the persistent EGFR activation that is sufficient to induce renal tubulointerstitial fibrosis. Mice with endothelial-specific knockout of HB-EGF had a reduction in Ang-II-mediated endothelial dysfunction, renal fibrosis, and inflammation (34). Furthermore, interstitial staining of a-SMA (green, a marker of myofibroblasts) and Ki-67 (red, a marker of cell proliferation) was visualized in the kidney by using immunofluorescence.…”

Deletion of the EGF receptor in vascular smooth muscle cells prevents chronic angiotensin II‐induced arterial wall stiffening and media thickening

“…Our data support a model where VSMC‐EGFR is required for vascular remodelling. Whether or not EGFR of vascular cells contribute to the inflammatory response has to be addressed in the future using more detailed immunological parameters and suitable genetic models, for example endothelial cell or macrophage specific EGFR knockouts. Of course, one has to bear in mind that there is also EGFR‐independent AII signalling that might contribute to the pathological effects …”