Targeted Inactivation of EGF Receptor Inhibits Renal Collecting Duct Development and Function

Zhang, Zhao; Pascuet, Elena; Hueber, Pierre-Alain; Chu, LeeLee; Bichet, Daniel G.; Lee, Tang-Cheng; Threadgill, David W.; Goodyer, Paul

doi:10.1681/asn.2009070719

Cited by 33 publications

(25 citation statements)

References 24 publications

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“…A similar result was reported by Breyer et al 80 when rabbit collecting tubules were perfused with EGF during stimulation by VP; a 50% inhibition by EGF of the hydraulic conductivity induced by VP in control tubules was noted. Zhang et al, 81 however, found that targeted inactivation of EGFR in renal collecting ducts induced moderate polyuria and reduced urine-concentrating ability, despite VP stimulation and normal AQP2 expression. This defect of water reabsorption in their study can, however, be explained by the significant anatomic abnormalities observed in these knockout mice.…”

Section: Discussionmentioning

confidence: 99%

EGF Receptor Inhibition by Erlotinib Increases Aquaporin 2–Mediated Renal Water Reabsorption

Cheung

Nomura

Nair

et al. 2016

JASN

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Nephrogenic diabetes insipidus (NDI) is caused by impairment of vasopressin (VP) receptor type 2 signaling. Because potential therapies for NDI that target the canonical VP/cAMP/protein kinase A pathway have so far proven ineffective, alternative strategies for modulating aquaporin 2 (AQP2) trafficking have been sought. Successful identification of compounds by our high-throughput chemical screening assay prompted us to determine whether EGF receptor (EGFR) inhibitors stimulate AQP2 trafficking and reduce urine output. Erlotinib, a selective EGFR inhibitor, enhanced AQP2 apical membrane expression in collecting duct principal cells and reduced urine volume by 45% after 5 days of treatment in mice with lithiuminduced NDI. Similar to VP, erlotinib increased exocytosis and decreased endocytosis in LLC-PK1 cells, resulting in a significant increase in AQP2 membrane accumulation. Erlotinib increased phosphorylation of AQP2 at Ser-256 and Ser-269 and decreased phosphorylation at Ser-261 in a dose-dependent manner. However, unlike VP, the effect of erlotinib was independent of cAMP, cGMP, and protein kinase A. Conversely, EGF reduced VP-induced AQP2 Ser-256 phosphorylation, suggesting crosstalk between VP and EGF in AQP2 trafficking and a role of EGF in water homeostasis. These results reveal a novel pathway that contributes to the regulation of AQP2-mediated water reabsorption and suggest new potential therapeutic strategies for NDI treatment.

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Section: Discussionmentioning

confidence: 99%

EGF Receptor Inhibition by Erlotinib Increases Aquaporin 2–Mediated Renal Water Reabsorption

Cheung

Nomura

Nair

et al. 2016

JASN

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“…Increased and/or altered expression of growth factors and receptors that regulate ureteric bud (UB) branching and collecting duct elongation in late stages of nephrogenesis (112)(113)(114)(115)(116)(117)(118) and promote tubular regeneration after renal injury (119-124) may play a role in PKD pathogenesis. These include members of the EGF family (EGF, TGF-α, heparin-binding EGF, and amphiregulin), HGF and IGF1, and their tyrosine kinase receptors, ErbB1 to ErbB4, MET, and IGF1R, respectively.…”

Section: Growth Factors/receptors As Targets For Pkd Treatmentmentioning

confidence: 99%

Genetic mechanisms and signaling pathways in autosomal dominant polycystic kidney disease

2014

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Recent advances in defining the genetic mechanisms of disease causation and modification in autosomal dominant polycystic kidney disease (ADPKD) have helped to explain some extreme disease manifestations and other phenotypic variability. Studies of the ADPKD proteins, polycystin-1 and -2, and the development and characterization of animal models that better mimic the human disease, have also helped us to understand pathogenesis and facilitated treatment evaluation. In addition, an improved understanding of aberrant downstream pathways in ADPKD, such as proliferation/secretion-related signaling, energy metabolism, and activated macrophages, in which cAMP and calcium changes may play a role, is leading to the identification of therapeutic targets. Finally, results from recent and ongoing preclinical and clinical trials are greatly improving the prospects for available, effective ADPKD treatments.

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“…Egfr null mutants alone also present with renal hypoplasia, characterized by atrophy of the renal papilla and decreased ureteric branching (20). Interestingly, conditional inactivation of Egfr in the UB lineage results in normal ureteric branching but a marked reduction in collecting duct elongation (20).…”

Section: Contribution Of the Ureteric Cell Lineage To Renal Hypoplasiamentioning

confidence: 99%

Genetics of Renal Hypoplasia: Insights Into the Mechanisms Controlling Nephron Endowment

et al. 2010

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ABSTRACT:Renal hypoplasia, defined as abnormally small kidneys with normal morphology and reduced nephron number, is a common cause of pediatric renal failure and adult-onset disease. Genetic studies performed in humans and mutant mice have implicated a number of critical genes, in utero environmental factors and molecular mechanisms that regulate nephron endowment and kidney size. Here, we review current knowledge regarding the genetic contributions to renal hypoplasia with particular emphasis on the mechanisms that control nephron endowment in humans and mice. R enal hypoplasia is a common, yet poorly understood and misused term describing congenital renal anomalies. Renal hypoplasia is defined as abnormally small kidneys (Ͻ2 SD below the expected mean when correlated with age or parameters of somatic growth) with normal morphology and reduced nephron number. This definition predicts that ϳ2.2% of the population exhibit renal hypoplasia, whereas epidemiologic studies suggest an estimated incidence of 1 in 400 births (1). Much confusion and the misapplication of this definition have arisen because the majority of congenitally small kidneys also exhibit evidence of tissue maldifferentiation, defined as renal dysplasia. The exact incidence of pure renal hypoplasia (without dysplasia) is difficult to define as renal dysplasia has often been incorrectly described as hypoplasia. This has predominantly been due to the lack of noninvasive diagnostic tools (i.e. Ultrasound) with resolution power adequate enough to discriminate dysplasia from hypoplasia in such settings. Severe reductions in nephron number that are characteristic of renal hypoplasia/dysplasia are the leading cause of childhood end stage renal disease. Indeed, if severe enough, these conditions can lead to significant impairment of intrauterine renal function which can in turn lead to the oligohydramnios sequence, a condition not compatible with extrauterine life. This includes severe and modest bilateral renal hypoplasia. More subtle defects in nephron number, such as those at the lower end of the normal range caused by mild bilateral renal hypoplasia, have been associated with the development of adult-onset hypertension and chronic renal failure (2-6). Here, we focus on knowledge derived from the study of human syndromic forms of renal hypoplasia and mouse mutants that provide insights into the molecular mechanisms that underlie renal hypoplasia and control nephron endowment. Congenital renal abnormalities characterized by nephron number and other renal pathologies including renal dysplasia, hydroureter, cystic dysplasia, and agenesis are reviewed in detail elsewhere (7-9). OVERVIEW OF KIDNEY DEVELOPMENTDevelopment of the mammalian metanephric kidney is dependent on reciprocal inductive interactions between two distinct cell lineages, the ureteric cell lineage and the metanephric mesenchyme (MM) cell lineage (Fig. 1). At the onset of metanephric development, signals emanating from the mass of uninduced MM initiate the formation of an epithelial bud (th...

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Targeted Inactivation of EGF Receptor Inhibits Renal Collecting Duct Development and Function

Cited by 33 publications

References 24 publications

EGF Receptor Inhibition by Erlotinib Increases Aquaporin 2–Mediated Renal Water Reabsorption

EGF Receptor Inhibition by Erlotinib Increases Aquaporin 2–Mediated Renal Water Reabsorption

Genetic mechanisms and signaling pathways in autosomal dominant polycystic kidney disease

Genetics of Renal Hypoplasia: Insights Into the Mechanisms Controlling Nephron Endowment

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