Deletion of ErbB4 accelerates polycystic kidney disease progression in cpk mice

Abstract

ErbB4 is highly expressed in the cystic kidneys with polycystic kidney diseases. To investigate its potential role in cystogenesis, cpk mice carrying a heart-rescued ErbB4 deletion were generated. Accelerated cyst progression and renal function deterioration were noted as early as 10 days postnatally in cpk mice with ErbB4 deletion compared to cpk mice, as indicated by increased cystic index, higher kidney weight to body weight ratios and elevated BUN levels. No apparent defects in renal development were noted with ErbB4 deletion itself. Increased cell proliferation was predominately seen in the cortex of cystic kidneys with or without ErbB4 deletion. However, there was significantly more cell proliferation in the cyst-lining epithelial cells in cpk mice with ErbB4 deletion. TUNEL staining localized apoptotic cells mainly to the renal medulla. There were significantly more apoptotic cells in the cyst-lining epithelial cells in ErbB4-deleted cpk kidneys, with decreased levels of cyclin D1, increased levels of p21, p27 and cleaved caspase 3. Thus, lack of ErbB4 may contribute to elevated cell proliferation and unbalanced cell apoptosis, resulting in accelerated cyst formation and early renal function deterioration. These studies suggest that the high level of ErbB4 expression seen in cpk mice may exert relative cytoprotective effects in renal epithelia.

MicroRNA-146b, a Sensitive Indicator of Mesenchymal Stem Cell Repair of Acute Renal Injury

“…Veikkolainen et al demonstrated that ErbB4 participates in the proliferation and polarization of renal epithelial cells and in the formation of ducts during kidney development [34]. In addition, a recent study reported that ErbB4 knockout accelerated the progression of polycystic kidney disease [35]. We have confirmed the direct regulation of ErbB4 by miR-146b through dual-luciferase reporter assays.…”

Absence of miR-146a in Podocytes Increases Risk of Diabetic Glomerulopathy via Up-regulation of ErbB4 and Notch-1

“…It shows minimal expression in the adult kidney. Although ErbB4 is highly up-regulated in the kidneys with polycystic kidney disease, its genetic deletion protected animals from polycystic kidney disease, suggesting a complex and unclear role for ErbB4 in development and disease pathogenesis (74). Here, our results show that ErbB4 is up-regulated in diabetic glomeruli and in podocytes, suggesting that it plays a role in diabetic podocyte injury.…”

Urinary EGF Receptor Ligand Excretion in Patients with Autosomal Dominant Polycystic Kidney Disease and Response to Tolvaptan

“…Recently, experimental studies have shown that activation of this EGF receptor by binding with the ligands EGF or TGF-a results in cyst formation in vitro (8) and in vivo (9). Inhibition of EGF receptor tyrosine kinase activity blocked tubular cyst formation in an in vitro system (14), blockade of EGF receptor resulted in attenuation of cystic disease in animal models (15,16), whereas ErbB4 knockout mice showed an accelerated cyst progression and renal function deterioration (17). Together, these experimental studies provide compelling evidence that the EGF receptor pathway is involved with disease progression in ADPKD.…”