Glucagon Receptor–Mediated Extracellular Signal–Regulated Kinase 1/2 Phosphorylation in Rat Mesangial Cells

Li, Xiao C.; Carretero, Oscar A.; Shao, Yinlin; Zhuo, Jia L.

doi:10.1161/01.hyp.0000197946.81754.0a

Cited by 34 publications

(54 citation statements)

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“…AVP stimulates V 2 receptors to increase cAMP production in the inner medulla, which activates PKA (23) and induces the insertion of AQP2 proteins in apical membranes (19). We measured total and phosphorylated ERK1/2 proteins in the inner medulla to determine whether a decrease in adenylyl cyclase III expression after the deletion of AT1a receptor signaling in Agtr1a Ϫ/Ϫ mice decreases phosphorylated ERK1/2, as previously described (26,27,30).…”

Section: Methodsmentioning

confidence: 97%

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AT_1a receptor signaling is required for basal and water deprivation-induced urine concentration in AT_1a receptor-deficient mice

Shao

Zhuo

2012

American Journal of Physiology-Renal Physiology

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Li XC, Shao Y, Zhuo JL. AT1a receptor signaling is required for basal and water deprivation-induced urine concentration in AT 1a receptor-deficient mice. Am J Physiol Renal Physiol 303: F746-F756, 2012. First published June 27, 2012 doi:10.1152/ajprenal.00644.2011It is well recognized that ANG II interacts with arginine vasopressin (AVP) to regulate water reabsorption and urine concentration in the kidney. The present study used ANG II type 1a (AT 1a) receptor-deficient (Agtr1a Ϫ/Ϫ ) mice to test the hypothesis that AT 1a receptor signaling is required for basal and water deprivation-induced urine concentration in the renal medulla. Eight groups of wild-type (WT) and Agtr1a Ϫ/Ϫ mice were treated with or without 24-h water deprivation and 1-desamino-8-D-AVP (DDAVP; 100 ng/h ip) for 2 wk or with losartan (10 mg/kg ip) during water deprivation. Under basal conditions, Agtr1a Ϫ/Ϫ mice had lower systolic blood pressure (P Ͻ 0.01), greater than threefold higher 24-h urine excretion (WT mice: 1.3 Ϯ 0.1 ml vs. Agtr1a Ϫ/Ϫ mice: 5.9 Ϯ 0.7 ml, P Ͻ 0.01), and markedly decreased urine osmolality (WT mice: 1,834 Ϯ 86 mosM/kg vs. Agtr1a Ϫ/Ϫ mice: 843 Ϯ 170 mosM/kg, P Ͻ 0.01), without significant changes in 24-h urinary Na ϩ excretion. These responses in Agtr1a Ϫ/Ϫ mice were associated with lower basal plasma AVP (WT mice: 105 Ϯ 8 pg/ml vs. Agtr1a Ϫ/Ϫ mice: 67 Ϯ 6 pg/ml, P Ͻ 0.01) and decreases in total lysate and membrane aquaporin-2 (AQP2; 48.6 Ϯ 7% of WT mice, P Ͻ 0.001) and adenylyl cyclase isoform III (55.6 Ϯ 8% of WT mice, P Ͻ 0.01) proteins. Although 24-h water deprivation increased plasma AVP to the same levels in both strains, 24-h urine excretion was still higher, whereas urine osmolality remained lower, in Agtr1a Ϫ/Ϫ mice (P Ͻ 0.01). Water deprivation increased total lysate AQP2 proteins in the inner medulla but had no effect on adenylyl cyclase III, phosphorylated MAPK ERK1/2, and membrane AQP2 proteins in Agtr1a Ϫ/Ϫ mice. Furthermore, infusion of DDAVP for 2 wk was unable to correct the urine-concentrating defects in Agtr1a Ϫ/Ϫ mice. These results demonstrate that AT 1a receptor-mediated ANG II signaling is required to maintain tonic AVP release and regulate V2 receptormediated responses to water deprivation in the inner medulla. angiotensin II; angiotensin II type 1a receptor; adenylyl cyclases; aquaporin 2; arginine vasopressin; inner medullary collecting ducts; urine concentration WATER REABSORPTION by the inner medulla plays an important role in maintaining basal body electrolytes and fluid balance, urine concentration, and blood pressure homeostasis. Physiologically, water transport in the inner medulla is primarily regulated by the neuropeptide hormone arginine vasopressin ([Arg 8 ]-AVP), which is released from the posterior pituitary in response to changes in extracellular fluid volume and plasma and urine osmolality (1,23,40). In the inner medulla of the kidney, AVP binds to G s protein-coupled type 2 (V 2 ) receptors expressed on basolateral membranes of principal cells, which activates adenylyl cyclases ...

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Section: Methodsmentioning

confidence: 97%

“…cAMP is the key second messenger that mediates the translocation of AQP2 from intracellular vesicles to apical membranes (10,11,22). cAMP also activates PKA and MAPK ERK1/2 (19,22,27,28). Activation of ERK1/2 may induce AQP2 phosphorylation, facilitating water transport in the collecting ducts.…”

Section: Or In Agtr1amentioning

confidence: 99%

AT_1a receptor signaling is required for basal and water deprivation-induced urine concentration in AT_1a receptor-deficient mice

Shao

Zhuo

2012

American Journal of Physiology-Renal Physiology

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“…We speculate that the different ERK1/2 activity might be caused by the complicated mechanisms involved in the control of ERK1/2 activity. In addition to well-known upstream cellular surface receptors and their downstream effectors, various hormone levels (including insulin, glucagon, and leptin) and nutritional status (including HFD and high-carbohydrate diet) and even self-signaling can influence ERK1/2 activity (17,38,39).…”

Section: Discussionmentioning

confidence: 99%

Activation of ERK1/2 Ameliorates Liver Steatosis in Leptin Receptor–Deficient (db/db) Mice via Stimulating ATG7-Dependent Autophagy

Xiao

Liu

et al. 2015

Diabetes

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Although numerous functions of extracellular signalregulated kinase 1/2 (ERK1/2) are identified, a direct effect of ERK1/2 on liver steatosis has not been reported. Here, we show that ERK1/2 activity is compromised in livers of leptin receptor-deficient (db/db) mice. Adenovirusmediated activation of mitogen-activated protein kinase kinase 1 (MEK1), the upstream regulator of ERK1/2, significantly ameliorated liver steatosis in db/db mice, increased expression of genes related to fatty acid b-oxidation and triglyceride (TG) export and increased serum b-hydroxybutyrate (3-HB) levels. Opposite effects were observed in adenovirus-mediated ERK1/2 knockdown C57/B6J wild-type mice. Furthermore, autophagy and autophagy-related protein 7 (ATG7) expression were decreased or increased by ERK1/2 knockdown or activation, respectively, in primary hepatocytes and liver. Blockade of autophagy by the autophagy inhibitor chloroquine or adenovirus-mediated ATG7 knockdown reversed the ameliorated liver steatosis in recombinant adenoviruses construct expressing rat constitutively active MEK1 Ad-CA MEK1 db/db mice, decreased expression of genes related to fatty acid b-oxidation and TG export, and decreased serum 3-HB levels. Finally, ERK1/2 regulated ATG7 expression in a p38-dependent pathway. Taken together, these results identify a novel beneficial role for ERK1/2 in liver steatosis via promoting ATG7-dependent autophagy, which provides new insights into the mechanisms underlying liver steatosis and important hints for targeting ERK1/2 in treating liver steatosis.Nonalcoholic fatty liver disease involves a serious pathological change in liver (1). The initial stage of nonalcoholic fatty liver disease is liver steatosis, characterized by the excess deposition of triglyceride (TG) and/or cholesterol (TC) in liver (2). If uncontrolled, liver steatosis will progress to life-threatening diseases, such as liver cirrhosis and dysfunction (3). Abnormal hepatic lipid accumulation results from increased uptake of fatty acid/augmented de novo lipogenesis and/or decreased b-oxidation/impaired TG export (4).Autophagy, a cellular process that degrades intracellular organelles and proteins (5), has recently been demonstrated to regulate lipid metabolism (6,7). Lipid droplets are sequestered by autophagosome with the coordination of autophagy-related genes (ATGs). Autophagosome is then fused with lysosome (8) for the degradation of lipid droplets into free fatty acids (FFAs). FFAs are then degraded by mitochondrial b-oxidation to produce ATP or are reesterified into TG for storage (9). Impaired autophagy decreases hepatic fatty acid b-oxidation (FAO) and TG export and results in liver steatosis in mice (7,10), and fatty liver is ameliorated when hepatic autophagy is stimulated by certain compounds (11,12) or some signaling pathways (13) in various animal models.The mitogen-activated protein kinase-extracellular signalregulated kinase (MEK-ERK) signaling pathway is involved in a wide variety of cellular processes (14-16). Several lines of evidence, ...

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“…These cells are derived from the rat kidney and show both characteristics of glomerular MCs and typical responses to Ang II and glucagon [15,25,27]. RPMI-1640 medium, trypsin, heatinactivated fetal bovine serum (FBS) and antibiotics (penicillin and streptomycin) were purchased from ATCC.…”

Section: Methodsmentioning

confidence: 99%

“…We have recently shown that glucagon stimulates MC growth and proliferation by inducing MAP kinase signaling via activation of cAMP-dependent PKA and phospholipase C [25]. However, we do not know whether these effects of glucagons involve interactions with Ang II or AT 1 /AT 2 receptor signaling.…”

Section: Introductionmentioning

confidence: 95%

Cross-talk between angiotensin II and glucagon receptor signaling mediates phosphorylation of mitogen-activated protein kinases ERK 1/2 in rat glomerular mesangial cells

Carretero

Zhuo

2006

Biochemical Pharmacology

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We have recently shown that the pancreatic hormone glucagons-induced phosphorylation of mitogen-activated protein (MAP) kinase ERK 1/2 as well as growth and proliferation of rat glomerular mesangial cells (MCs) via activation of cAMP-dependent protein kinase A (PKA)-and phospholipase C (PLC)/Ca 2+ -mediated signaling pathways. Since circulating glucagon and tissue angiotensin II (Ang II) levels are inappropriately elevated in type 2 diabetes, we tested the hypothesis that glucagon induces phosphorylation of ERK 1/2 in MCs by interacting with Ang II receptor signaling. Stimulation of MCs by glucagon (10 nM) induced a marked increase in intracellular [Ca 2+ ] i that was abolished by [Des-His 1 , Glu 9 ]-glucagon (1 μM), a selective glucagon receptor antagonist. Both glucagon and Ang II-induced ERK 1/2 phosphorylation (glucagon: 214 ± 14%; Ang II: 174 ± 16%; p < 0.001 versus control), and these responses were inhibited by the AT 1 receptor blocker losartan (glucagon + losartan: 77 ± 14%; Ang II + losartan: 84 ± 18%; p < 0.01 versus glucagon or Ang II) and the AT 2 receptor blocker PD 123319 (glucagon + PD: 78 ± 7%; Ang II + PD: 87 ± 7%; p < 0.01 versus glucagon or Ang II). Inhibition of cAMP-dependent PKA with H89 (1 μM) or PLC with U73122 (1 μM) also markedly attenuated the phosphorylation of ERK 1/2 induced by glucagon (glucagon + U73122: 109 ± 15%; glucagon + H89: 113 ± 16%; p < 0.01 versus glucagon) or Ang II (Ang II + U73122: 111 ± 13%; Ang II + H89: 86 ± 10%; p < 0.01 versus Ang II). Wortmannin (1 μM), a selective PI 3-kinase inhibitor, also blocked glucagon-or Ang II-induced ERK 1/2 phosphorylation. These results suggest that AT 1 receptor-activated cAMP-dependent PKA, PLC and PI 3-kinase signaling is involved in glucagon-induced MAP kinase ERK 1/2 phosphorylation in MCs. The inhibitory effect of PD 123319 on glucagon-induced ERK 1/2 phosphorylation further suggests that AT 2 receptors also play a similar role in this response.

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Glucagon Receptor–Mediated Extracellular Signal–Regulated Kinase 1/2 Phosphorylation in Rat Mesangial Cells

Cited by 34 publications

References 33 publications

AT_1a receptor signaling is required for basal and water deprivation-induced urine concentration in AT_1a receptor-deficient mice

AT_1a receptor signaling is required for basal and water deprivation-induced urine concentration in AT_1a receptor-deficient mice

Activation of ERK1/2 Ameliorates Liver Steatosis in Leptin Receptor–Deficient (db/db) Mice via Stimulating ATG7-Dependent Autophagy

Cross-talk between angiotensin II and glucagon receptor signaling mediates phosphorylation of mitogen-activated protein kinases ERK 1/2 in rat glomerular mesangial cells

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Glucagon Receptor–Mediated Extracellular Signal–Regulated Kinase 1/2 Phosphorylation in Rat Mesangial Cells

Cited by 34 publications

References 33 publications

AT1a receptor signaling is required for basal and water deprivation-induced urine concentration in AT1a receptor-deficient mice

AT1a receptor signaling is required for basal and water deprivation-induced urine concentration in AT1a receptor-deficient mice

Activation of ERK1/2 Ameliorates Liver Steatosis in Leptin Receptor–Deficient (db/db) Mice via Stimulating ATG7-Dependent Autophagy

Cross-talk between angiotensin II and glucagon receptor signaling mediates phosphorylation of mitogen-activated protein kinases ERK 1/2 in rat glomerular mesangial cells

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AT_1a receptor signaling is required for basal and water deprivation-induced urine concentration in AT_1a receptor-deficient mice

AT_1a receptor signaling is required for basal and water deprivation-induced urine concentration in AT_1a receptor-deficient mice