Nerve growth factor regulates   HCO  3   −     absorption in thick  ascending limb: modifying effects of vasopressin

Growth factors stimulate Na+/H+exchange activity in many cell types but their effects on acid secretion via this mechanism in renal tubules are poorly understood. We examined the regulation of [Formula: see text]absorption by nerve growth factor (NGF) in the rat medullary thick ascending limb (MTAL), which absorbs [Formula: see text]via apical membrane Na+/H+exchange. MTAL were perfused in vitro with 25 mM[Formula: see text] solutions (pH 7.4; 290 mosmol/kgH2O). Addition of 0.7 nM NGF to the bath decreased [Formula: see text]absorption from 13.1 ± 1.1 to 9.6 ± 0.8 pmol ⋅ min−1 ⋅ mm−1( P < 0.001). In contrast, with 10−10 M arginine vasopressin (AVP) in the bath, addition of NGF to the bath increased[Formula: see text] absorption from 8.0 ± 1.6 to 12.5 ± 1.3 pmol ⋅ min−1 ⋅ mm−1( P < 0.01). Both effects of NGF were blocked by genistein, consistent with the involvement of tyrosine kinase pathways. However, the AVP-dependent stimulation required activation of protein kinase C (PKC), whereas the inhibition was PKC independent, indicating that the NGF-induced signaling pathways leading to inhibition and stimulation of [Formula: see text]absorption are distinct. Hypertonicity blocked the inhibition but not the AVP-dependent stimulation, suggesting that hypertonicity and NGF may inhibit [Formula: see text] absorption via a common mechanism. These data demonstrate that NGF inhibits[Formula: see text] absorption in the MTAL under basal conditions but stimulates [Formula: see text]absorption in the presence of AVP, effects that are mediated through distinct signal transduction pathways. They also show that AVP is a critical determinant of the response of the MTAL to growth factor stimulation and suggest that NGF can either inhibit or stimulate apical Na+/H+ exchange activity depending on its interactions with other regulatory factors. Locally produced growth factors such as NGF may play a role in regulating renal tubule [Formula: see text] absorption.

Download Full-text

ERK mediates inhibition of Na+/H+exchange and HCO 3 − absorption by nerve growth factor in MTAL

AJP Renal Physiology ◽

10.1152/ajprenal.00133.2001 ◽

2002 ◽

Vol 282 (6) ◽

pp. F1056-F1063 ◽

Cited By ~ 29

Author(s):

Bruns A. Watts ◽

David W. Good

Keyword(s):

Nerve Growth Factor ◽

Growth Factor ◽

Map Kinase ◽

Map Kinases ◽

Basolateral Membrane ◽

Renal Tubules ◽

Thick Ascending Limb ◽

Nerve Growth ◽

Erk Activation ◽

Exchange Activity

Mitogen-activated protein (MAP) kinases mediate a variety of critical cellular events, but their role in the regulation of epithelial transport is largely undefined. Recently, we demonstrated that nerve growth factor (NGF) inhibits HCO[Formula: see text] absorption in the rat medullary thick ascending limb (MTAL) through an unusual mechanism: 1) NGF inhibits basolateral membrane Na+/H+ exchange activity, an effect opposite to the stimulation of Na+/H+ exchange by growth factors in other cells; and 2) inhibition of basolateral Na+/H+ exchange results secondarily in inhibition of apical Na+/H+ exchange, thereby inhibiting HCO[Formula: see text] absorption. In this study, we examined the role of MAP kinases in mediating inhibition by NGF. In tissue strips from the inner stripe of the outer medulla and in microdissected MTALs, NGF increased extracellular signal-regulated kinase (ERK) activity twofold but had no effect on c-Jun NH2-terminal kinase (JNK) or p38 MAP kinase activity. The selective MAP kinase kinase (MEK1/2) inhibitors U0126 and PD-98059 abolished the NGF-induced ERK activation and largely eliminated (≥60%) the effects of NGF to inhibit basolateral Na+/H+ exchange activity and transepithelial HCO[Formula: see text] absorption in perfused MTALs. The MEK1/2 inhibitors did not affect inhibition of HCO[Formula: see text]absorption by bath ethylisopropyl amiloride, indicating that ERK activation is not involved in mediating interaction between the basolateral and apical Na+/H+ exchangers. These results demonstrate that NGF inhibits basolateral Na+/H+ exchange activity and HCO[Formula: see text] absorption in the MTAL through activation of the ERK signaling pathway. These findings identify a novel action of ERK to inhibit Na+/H+ exchange activity and establish a role for MAP kinase pathways in the acute regulation of Na+/H+ exchange activity and transepithelial acid secretion in renal tubules.

Download Full-text

Inhibition of Ethanol Neurotoxicity by Treatment with Growth Factors and Estrogen

McGill Journal of Medicine ◽

10.26443/mjm.v5i1.650 ◽

2020 ◽

Vol 5 (1) ◽

Author(s):

Jason Zell ◽

Jeremy Montague ◽

Tomas Lopez ◽

Mudd Laura

Keyword(s):

Growth Factors ◽

Nerve Growth Factor ◽

Growth Factor ◽

Ethanol Ingestion ◽

Fetal Alcohol ◽

Simultaneous Treatment ◽

Nerve Growth ◽

Neuronal Viability ◽

Igf I

Ethanol ingestion by pregnant women is the primary cause of fetal alcohol syndrome, which is characterized by brain abnormalities and decreased mental capacity. In the present study,cultured neurons from embryonic rat cortices were used to study the effects of ethanol on cell survival and the potential for neuroprotection by certain growth factors and estrogen. Neurons were grown in the presence of a glial plane and in the absence of serum. Survival was assessed following chronic treatment with ethanol (45 mM) in the presence and absence of either nerve growth factor (NGF, 100ng/ml), basic fibroblast growth factor (bFGF, 5ng/ml), insulin-like growth factor I or II (IGF-I, IGF-II, both 10ng/ml), or estrogen (Es, 10nM) added on days one and four in vitro. On day in vitro 4 (DIV4) ethanol effects on neuronal viability were significantly prevented by NGF, bFGF, IGF-I, and Es. DIV6 survival of ethanol-treated neurons was increased significantly by treatment with NGF, bFGF, IGF-I, IGF-II, and Es. Nerve growth factor, bFGF, and IGF-I effects were shown to be dose-dependent. Administration of 1-100 ng/ml NGF, 0.05-5 ng/ml bFGF and 0.1-10ng/ml IGF-I led to statistically significant effects at 10, 5, and 1 ng/ml, respectively. Thus, ethanol’s effect on neuronal survival may be inhibited by simultaneous treatment with physiological doses of these factors.

Download Full-text

Proangiogene und Tumor fördernde Eigenschaften des Nerve Growth Factor auf murine Lungenkarzinome in vitro

Pneumologie ◽

10.1055/s-0029-1247948 ◽

2010 ◽

Vol 64 (01) ◽

Author(s):

KM Seidler ◽

H Renz ◽

WA Nockher

Keyword(s):

Nerve Growth Factor ◽

Growth Factor ◽

Nerve Growth

Download Full-text

Neuroprotective and anti-amnestic effects of a combination therapy in a model of photochemical ischemic damage in the prefrontal cortex

ZHurnal «Patologicheskaia fiziologiia i eksperimental`naia terapiia» ◽

10.25557/0031-2991.2018.02.39-45 ◽

2018 ◽

pp. 39-45

Author(s):

Ф.М. Шакова ◽

Т.И. Калинина ◽

М.В. Гуляев ◽

Г.А. Романова

Keyword(s):

Prefrontal Cortex ◽

Nerve Growth Factor ◽

Growth Factor ◽

Combination Therapy ◽

Neuroprotective Effect ◽

Regulatory Protein ◽

Human Growth ◽

Neuroprotective Effects ◽

Nerve Growth

Цель исследования - изучение влияния комбинированной терапии (мутантные молекулы эритропоэтина (EPO) и дипептидный миметик фактора роста нервов ГК-2H) на воспроизведение условного рефлекса пассивного избегания (УРПИ) и объем поражения коры мозга у крыс с двусторонним ишемическим повреждением префронтальной коры. Методика. Мутантные молекулы EPO (MЕРО-TR и MЕPО-Fc) с значительно редуцированной эритропоэтической и выраженной цитопротекторной активностью созданы методом генной инженерии. Используемый миметик фактора роста нервов человека, эндогенного регуляторного белка, в экспериментах in vitro проявлял отчетливые нейропротективные свойства. Двустороннюю фокальную ишемию префронтальной коры головного мозга крыс создавали методом фотохимического тромбоза. Выработку и оценку УРПИ проводили по стандартной методике. Объем повреждения мозга оценивался при помощи МРТ. MEPO-TR и MEPO-Fc (50 мкг/кг) вводили интраназально однократно через 1 ч после фототромбоза, ГК-2Н (1 мг/кг) - внутрибрюшинно через 4 ч после фототромбоза и далее в течение 4 послеоперационных суток. Результаты. Выявлено статистически значимое сохранение выработанного до ишемии УРПИ, а также значимое снижение объема повреждения коры при комплексной терапии. Полученные данные свидетельствуют об антиамнестическом и нейропротекторном эффектах примененной комбинированной терапии, которые наиболее отчетливо выражены в дозах: МEPO-Fc (50 мкг/кг) и ГК-2Н (1 мг/кг). Заключение. Подтвержден нейропротекторный эффект и усиление антиамнестического эффекта при сочетанном применении мутантных производных эритропоэтина - MEPO-TR и MEPO-Fc и дипептидного миметика фактора роста нервов человека ГК-2H. The aim of this study was to investigate the effect of combination therapy, including mutant erythropoietin molecules (EPO) and a dipeptide mimetic of the nerve growth factor, GK-2H, on the conditioned passive avoidance (PA) reflex and the volume of injury induced by bilateral ischemia of the prefrontal cortex in rats. Using the method of genetic engineering the mutant molecules of EPO, MERO-TR and MEPO-Fc, with strongly reduced erythropoietic and pronounced cytoprotective activity were created. The used human nerve growth factor mimetic, an endogenous regulatory protein based on the b-bend of loop 4, which is a dimeric substituted dipeptide of bis- (N-monosuccinyl-glycyl-lysine) hexamethylenediamine, GK-2 human (GK-2H), has proven neuroprotective in in vitro experiments. Methods. Bilateral focal ischemic infarction was modeled in the rat prefrontal cortex by photochemically induced thrombosis. The PA test was performed according to a standard method. Volume of brain injury was estimated using MRI. MEPO-TR, and MEPO-Fc (50 mg/kg, intranasally) were administered once, one hour after the injury. GK-2Н (1 mg/kg, i.p.) was injected four hours after the injury and then for next four days. Results. The study showed that the complex therapy provided statistically significant retention of the PA reflex developed prior to ischemia and a significant decrease in the volume of injury. The anti-amnestic and neuroprotective effects of combination therapy were most pronounced at doses of MEPO-Fc 50 mg/kg and GK-2H 1 mg/kg. Conclusion. This study has confirmed the neuroprotective effect and enhancement of the anti-amnestic effect exerted by the combination of mutant erythropoietin derivatives, MEPO-TR and MEPO-Fc, and the dipeptide mimetic of human growth factor GK-2H.

Download Full-text