Heparin-Binding EGF-Like Growth Factor Is Up-Regulated in the Obstructed Kidney in a Cell- and Region-Specific Manner and Acts to Inhibit Apoptosis

Abstract

The expression of certain growth factors in the epidermal growth factor (EGF) family is altered in response to renal injury. Recent studies have demonstrated that heparin binding EGF-like growth factor (HB-EGF) expression may be cytoprotective in response to apoptotic signals. The purpose of this study was to investigate the potential role of HB-EGF in the upper urinary tract following unilateral ureteral obstruction. We present evidence that: i) ureteral obstruction induced cell-specific but transient activation of HB-EGF gene expression; ii) HB-EGF expression in renal epithelial cells increased under conditions where mechanical deformation, such as that caused by hydronephrotic distension, induces apoptosis, but HB-EGF expression did not increase in renal pelvis smooth muscle cells under identical conditions; and iii) enforced expression of HB-EGF served to protect renal epithelial cells from stretch-induced apoptosis. These results suggest a potential mechanism by which the kidney protects itself from apoptosis triggered by urinary tract obstruction.

ERAD‐dependent control of the Wnt secretory factor Evi

“…Cells were harvested 48 h after transfection. The following expression constructs were used: pSpCas9(BB)‐2A‐Puro (px459; Addgene #48139; Ran et al , 2013), psPAX2 (Addgene #12260; D. Trono), pMD2.G‐VSVG (Addgene #12259; D. Trono), TCF4/Wnt‐Firefly Luciferase (Demir et al , 2013), Actin‐Renilla Luciferase (Nickles et al , 2012), pcDNA3‐Wnt11 (Addgene #35922; Najdi et al , 2012), pcDNA3‐Wnt10B, (Addgene #35921; Najdi et al , 2012), pcDNA3‐Wnt16 (Addgene #35923; Najdi et al , 2012), pcDNA3‐Wnt7B (Addgene #35915; Najdi et al , 2012), pcDNA3‐Wnt8 (Addgene #35916; Najdi et al , 2012), pcDNA3‐Wnt5A (Addgene #35911; Najdi et al , 2012), pcDNA3‐Wnt3A (Addgene #35908; Najdi et al , 2012), pcDNA3‐Wnt3 (Addgene #35909; Najdi et al , 2012), pcDNA3.2‐Wnt3A‐V5 (Addgene #43810; MacDonald et al , 2014), pcDNA3‐IGFBP5‐V5 (Addgene #11608; S. Johnson), pcDNA3‐EGF‐Myc (Addgene #11601; Nguyen et al , 2000), VCP(wt)‐EGFP (Addgene #23971; Tresse et al , 2010), VCP(DKO)‐EGFP (Addgene #23974; Tresse et al , 2010), pCMV6‐Myc‐DDK‐tagged PORCN (Origene # RC223764), sLuc (Katanaev et al , 2008), pCS2(+)‐mWnt3A (C. Niehrs), pCS2(+)‐Dvl3 (C. Niehrs), pCS2(+)‐mWnt3A‐S209A (Kumar et al , 2014), and β‐Catenin‐YFP (Stemmer et al , 2008). To generate C‐terminally FLAG‐HA‐tagged CGRRF1 and Hrd1, the FLAG‐HA sequence was inserted into the pcDNA5‐FRT/TO vector (Invitrogen).…”

Hsp70/nitric oxide relationship in apoptotic modulation during obstructive nephropathy

“…Because of the significant role of apoptosis in the pathogenesis of renal cellular injury resulting from urinary tract obstruction, factors regulating the renal apoptotic response have been studied (Chevalier 2006). Stretching of the renal tubular cells by increased hydrostatic pressure provides a powerful mechanical stimulus to apoptosis in the obstructed kidney (Nguyen et al 2000;Manucha et al 2007). Ischemia is another stimulus to apoptosis, and UUO induces a sharp reduction in renal blood flow as well as impairment of autoregulation of renal blood flow (Chevalier and Thornhill 1995).…”

Local overexpression of HB-EGF exacerbates remodeling following myocardial infarction by activating noncardiomyocytes

“…HB-EGF may play a role in the development of atherosclerosis resulting from smooth muscle cell hyperplasia, 4,7,8 pulmonary hypertension, and oncogenic transformation. 9,10 In contrast, HB-EGF is therapeutic for the skin, 11,12 kidney, 13,14 liver, and small intestine. 3,5,15,16 HB-EGF is markedly upregulated during the acute phase of injury and plays an essential role in epithelial cell repair, proliferation and regeneration in these organs.…”

“…3,5,15,16 HB-EGF is markedly upregulated during the acute phase of injury and plays an essential role in epithelial cell repair, proliferation and regeneration in these organs. 5,11,13,15,17 Further direct evidence of therapeutic benefit was provided by studies of administration of recombinant HB-EGF in animal ischemic disease models. 16 Thus, HB-EGF plays a number of physiological roles, and its effects are diverse and even opposing in nature depending on the tissues examined.…”