Deletion of the epidermal growth factor receptor in renal proximal tubule epithelial cells delays recovery from acute kidney injury

Abstract

To determine the role of epidermal growth factor receptor (EGFR) activation in renal functional and structural recovery from acute kidney injury (AKI), we generated mice with a specific EGFR deletion in the renal proximal tubule (EGFRptKO). Ischemia–reperfusion injury markedly activated EGFR in control littermate mice; however, this was inhibited in either the knockout or wild-type mice given erlotinib, a specific EGFR tyrosine kinase inhibitor. Blood urea nitrogen and serum creatinine increased to a comparable level in EGFRptKO and control mice 24 h after reperfusion, but the subsequent rate of renal function recovery was markedly slowed in the knockout mice. Twenty-four hours after reperfusion, both the knockout and the inhibitor-treated mice had a similar degree of histologic renal injury as control mice, but at day 6 there was minimal evidence of injury in the control mice while both EGFRptKO and erlotinib-treated mice still had persistent proximal tubule dilation, epithelial simplification, and cast formation. Additionally, renal cell proliferation was delayed due to decreased ERK and Akt signaling. Thus, our studies provide both genetic and pharmacologic evidence that proximal tubule EGFR activation plays an important role in the recovery phase after acute kidney injury.

Conditional Knockout of Proximal Tubule Mitofusin 2 Accelerates Recovery and Improves Survival after Renal Ischemia

“…Because no difference in the rate of cell proliferation was detected in the absence of ischemic stress, we hypothesize that the antiproliferative effect of Mfn2 is evident only in the presence of signals that activate Ras/ERK. The observation that Ras and ERK are activated by renal ischemia 36 in response to multiple growth factors, including hepatocyte growth factor, 37 EGF, 14 PDGF, 38 TGF-b, 31 and IGF, 39 support this contention. Importantly, an established ERK inhibitor completely prevented the increase in ERK activation ( Figure 6, C and D) and cell proliferation ( Figure 5) caused by Mfn2 deficiency.…”

“…After renal ischemia, extracellular regulated kinases (ERK) have been implicated in promoting cell proliferation and repair. [14][15][16] Although in vitro studies, including our own, provide a strong link between mitofusins and PT cell apoptosis, 1,4 the hypothesis that mitofusins regulate ischemic AKI in vivo has not been directly tested. On one hand, selective deletion of Mfn2 in the PT might aggravate ischemic AKI by increasing renal cell apoptosis.…”

“…4 However, Mfn2 (previously known as hyperplasia suppressor gene or HSG) could also exert potent "off target" effects on cell proliferation through p21Ras that are independent of mitochondrial dynamics. 11,12 If Mfn2 suppressed proliferation, a major contributor to renal recovery after stress, 14,16 then reducing Mfn2 in the PT might accelerate organ recovery. To assess the role of cell type-specific Mfn2 in mediating organ dysfunction after ischemia, we conditionally manipulated Mfn2 expression in the PT epithelial cell, a primary target of ischemic stress.…”

EGF Receptor Deletion in Podocytes Attenuates Diabetic Nephropathy

“…In this regard, we recently reported increased expression of the EGFR ligand, HB-EGF, in diabetes that was mediated by endothelial dysfunction, and endothelial-specific HB-EGF deletion reduced progression of diabetic nephropathy. 34 Previous studies by us and others indicated that activation of EGFR contributes to recovery from AKI [35][36][37] by accelerating tissue regeneration but is detrimental in response to chronic kidney insults by increasing profibrotic pathways. We suggest that mild or moderate AKI induces acute and self-limited EGFR activation to promote cell repair and proliferation, whereas more severe AKI or a continuous chronic kidney injury will induce continued EGFR activation, which in turn will activate TGF-b and other signaling pathways mediating progressive renal fibrosis.…”

Cellular and Molecular Mechanisms of AKI

“…Examples of receptors involved in AKI-mediated injury include the FAS receptor and TGFb receptor. 40,41 Examples of receptors involved in epithelial cytoprotection and repair include the EGF receptor, 42 HGF receptor (c-Met), 43 sphingosine-1-phosphate receptor, 44 and netrin-1 receptor. 45 Many questions relating to the role of receptors in AKI remain unanswered, including the sources of the putative ligands, mechanisms of receptor activation, and signaling pathways involved in protection from injury or involved with epithelial repair.…”