Transforming growth factor-β1 and phosphatases modulate COX-2 protein expression and TAU phosphorylation in cultured immortalized podocytes

Abdallah, Maya; Kennedy, C. R.; Stephan, Joseph S.; Khalil, Pamela Abou; Mroueh, Mohammad; Eid, Assaad A.; Faour, Wissam H.

doi:10.1007/s00011-017-1110-y

Cited by 10 publications

(11 citation statements)

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“…Podocyte injury is mostly associated with foot processes effacement leading to podocyte detachment or apoptosis. 7 In this study, we also found that ghrelin induced TAU phosphorylation. 44 Recently, we found that PGE2 can significantly modulate TAU protein phosphorylation.…”

Section: Discussionsupporting

confidence: 67%

“…5 Finally, overexpression of COX predisposed to albuminuria and caused podocyte damage. 7,8 Also, stimulation of podocytes with PGE2 reduced AKT phosphorylation levels, a survival kinase that protects podocytes from cell death induced by advanced glycation end products. 7,8 Also, stimulation of podocytes with PGE2 reduced AKT phosphorylation levels, a survival kinase that protects podocytes from cell death induced by advanced glycation end products.…”

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confidence: 99%

“…8 Finally, ERK1/2 mediated high glucose-induced VEGF secretion plays a harmful role in DN. 7 Ghrelin is an orexigenic gutderived acylated peptide 13 that regulates energy homeostasis and stimulates growth hormone release. 12 Recently, we showed that transforming growth factor-β1 (TGF-β1) and prostaglandin E2 significantly modulated TAU protein phosphorylation, and high glucose conditions potentiated TGF-β1 mediated COX-2 protein upregulation.…”

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confidence: 99%

“…6 Prostaglandin E2 and mechanical stress can activate p38 MAPK, a harmful pathway in podocytes. 7,8 Also, stimulation of podocytes with PGE2 reduced AKT phosphorylation levels, a survival kinase that protects podocytes from cell death induced by advanced glycation end products. 9,10 Also, PGE2 upregulated COX-2 protein through a restricted EP4/cAMP/AMPK/P38 MAPK pathway.…”

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confidence: 99%

“…12 Recently, we showed that transforming growth factor-β1 (TGF-β1) and prostaglandin E2 significantly modulated TAU protein phosphorylation, and high glucose conditions potentiated TGF-β1 mediated COX-2 protein upregulation. 7 Ghrelin is an orexigenic gutderived acylated peptide 13 that regulates energy homeostasis and stimulates growth hormone release. 14,15 It acts through various intracellular signalling cascades.…”

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confidence: 99%

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Ghrelin modulates intracellular signalling pathways that are critical for podocyte survival

Zein

Abdallah

Daher

et al. 2019

Cell Biochemistry & Function

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Damage to podocytes is a key event in glomerulopathies. While energy dense food can contribute to kidney damage, the role of the orixegenic hormone "ghrelin" in podocyte biology is still unknown. In the present study, we investigated the effect of ghrelin on podocyte survival as well as the signalling pathways mediating ghrelin effect in immortalized cultured rat podocytes. RT-PCR analysis revealed that GHS-R1 is expressed in rat podocytes. Western blot analysis showed that ghrelin upregulated COX-2 protein expression in a time and dose-dependent manner. Additionally, ghrelin activated P38 MAPK, AKT, and ERK1/2 pathways and also induced P38 MAPK phosphorylation in high glucose conditions. Ghrelin induced ROS release and dose dependently reduced podocyte survival. Ghrelin mediated podocyte cell death was partially reversed by pharmacologically inhibiting P38 MAPK or phospholipase C (PLC). Furthermore, PLC inhibitor (U73122) inhibited ghrelin induced P38 MAPK activation. While PI3K inhibitor (LY294002) was without effect on cell survival or P38 MAPK activation, it inhibited ghrelin induced ERK1/2 phosphorylation. Finally, ghrelin induced TAU phosphorylation was reversed by pharmacologic inhibitors of either P38 MAPK or PKA. In conclusion, ghrelin activated harmful molecular pathways in podocytes that can be damaging to the glomerular filtration barrier Significance of the study: Endocrine derangements secondary to obesity are major players in the aetiology of renal injuries. Furthermore, energy dense diet is thought to be the major element in developing obesity. Appetite and increase in energy intake are regulated by complex hormonal pathways which mainly include the orexigenic hormone "ghrelin" in addition to leptin. To date no study have highlighted a significant role for ghrelin in kidney biology, and therefore, it is thought that its endocrine effect is mostly limited to adipose tissue metabolism and appetite regulation. In this study, we first showed that ghrelin receptor is expressed on glomerular podocytes.Also, ghrelin showed negative impact on podocyte survival through modulating signalling pathways such as P38 MAPK and AKT known to play a key role in podocyte health. Moreover, the negative effects of ghrelin on podocytes were further exacerbated in hyperglycemic conditions. Of note, podocytes contribute to the formation and the maintenance of the glomerular filtration barrier and thus are important for Nabil El Zein and Maya S. Abdallah contributed equally to this work.

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Section: Discussionsupporting

confidence: 67%

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confidence: 99%

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confidence: 99%

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confidence: 99%

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confidence: 99%

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