Epidermal growth factors in the kidney and relationship to hypertension

Staruschenko, Alexander; Palygin, Oleg; Ilatovskaya, Daria V.; Pavlov, Tengis S.

doi:10.1152/ajprenal.00112.2013

Cited by 39 publications

(37 citation statements)

References 133 publications

(129 reference statements)

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“…[65][66][67] EGFRs are localized along the nephron, 65 and they play key roles in normal kidney physiology and pathogenesis. For example, EGF is important in renal cyst formation, 68 repair of AKI, 67 progression in CKD, 67,69 and development of kidney carcinoma. [70][71][72] At the cellular level, EGF is especially critical in renal sodium 69,73 and magnesium homeostasis.…”

Section: Discussionmentioning

confidence: 99%

“…For example, EGF is important in renal cyst formation, 68 repair of AKI, 67 progression in CKD, 67,69 and development of kidney carcinoma. [70][71][72] At the cellular level, EGF is especially critical in renal sodium 69,73 and magnesium homeostasis. 74,75 Therefore, it is The phosphoserine band intensities were normalized by their respective total AQP2 loading controls (mean6SD; n=4).…”

Section: Discussionmentioning

confidence: 99%

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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%

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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“…Dominant negative EGFR overexpression mice exhibited less interstitial fibrosis than wild type mice after subtotal renal ablation or following angiotensin II infusion (18). It was also reported that EGF-EGFR axis regulates sodium transport and development of hypertension (19). In this point of view, decreased EGF may be beneficial by inhibiting the activation of EGFR.…”

Section: Ju Et Al In Sci Transl Medmentioning

confidence: 95%

Epidermal growth factor as a prognostic biomarker in chronic kidney diseases

Isaka¹

2016

Ann. Transl. Med.

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“…Many investigators have studied the role of EGF and EGFR in the ENaC regulation [44,45], however the contradictory results have been reported [44,45]. Taruno et al [26] have report that an inhibitor of EGFR diminishes the ENaC-mediated Na + transport in renal A6 epithelial cells by activating EGFR via the change in the membrane tension caused by hypotonicity, suggesting that activation of EGFR would have a stimulatory action on the ENaC-mediated Na + transport in renal A6 epithelial cells.…”

Section: Cellular Physiology and Biochemistrymentioning

confidence: 99%

Action of Protein Tyrosine Kinase Inhibitors on the Hypotonicity-Stimulated Trafficking Kinetics of Epithelial Na+ Channels (ENaC) in Renal Epithelial Cells: Analysis Using a Mathematical Model

Marunaka

Taruno

Yamamoto

et al. 2018

Cell Physiol Biochem

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Background/Aims: Epithelial Na₊ channels (ENaCs) play crucial roles in control of blood pressure by determining the total amount of renal Na₊ reabsorption, which is regulated by various factors such as aldosterone, vasopressin, insulin and osmolality. The intracellular trafficking process of ENaCs regulates the amount of the ENaC-mediated Na₊ reabsorption in the collecting duct of the kidney mainly by determining the number of ENaC expressed at the apical membrane of epithelial cells. Although we previously reported protein tyrosine kinases (PTKs) contributed to the ENaC-mediated epithelial Na₊ reabsorption, we have no information on the role of PTKs in the intracellular ENaC trafficking. Methods: Using the mathematical model recently established in our laboratory, we studied the effect of PTKs inhibitors (PTKIs), AG1296 (10 µM: an inhibitor of the PDGF receptor (PDGFR)) and AG1478 (10 µM: an inhibitor of the EGF receptor (EGFR)) on the rates of the intracellular ENaC trafficking in renal epithelial A6 cells endogenously expressing ENaCs. Results: We found that application of PTKIs significantly reduced the insertion rate of ENaC to the apical membrane by 56%, the recycling rate of ENaC by 83%, the cumulative time of an individual ENaC staying in the apical membrane by 27%, the whole life-time after the first insertion of ENaC by 47%, and the cumulative Na₊ absorption by 61%, while the degradation rate was increased to 3.8-fold by application of PTKIs. These observations indicate that PTKs contribute to the processes of insertion, recycling and degradation of ENaC in the intracellular trafficking process under a hypotonic condition. Conclusion: The present study indicates that application of EGFR and PDGFR-inhibitable PTKIs reduced the insertion rate (k_I), and the recycling rate (k_R) of ENaCs, but increased degradation rate (k_D) in renal A6 epithelial cells under a hypotonic condition. These observations indicate that hypotonicity increases the surface expression of ENaCs by increasing the insertion rate (k_I) and the recycling rate (k_R) of ENaCs associated with a decrease in the degradation rate but without any significant effects on the endocytotic rate (k_E) in EGFR and PDGFR-related PTKs-mediated pathways.

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Epidermal growth factors in the kidney and relationship to hypertension

Cited by 39 publications

References 133 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

Epidermal growth factor as a prognostic biomarker in chronic kidney diseases

Action of Protein Tyrosine Kinase Inhibitors on the Hypotonicity-Stimulated Trafficking Kinetics of Epithelial Na+ Channels (ENaC) in Renal Epithelial Cells: Analysis Using a Mathematical Model

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