Circulating inhibitor of gonadotropin releasing hormone secretion by hypothalamic neurons in uremia
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Circulating inhibitor of gonadotropin releasing hormone secretion by hypothalamic neurons in uremia. / Daschner, Markus; Philippin, Bärbel; Nguyen, Trang; Wiesner, Rudolf J; Walz, Claudia; Oh, Jun; Sandow, Jürgen; Mehls, Otto; Schaefer, Franz.
in: KIDNEY INT, Jahrgang 62, Nr. 5, 11.2002, S. 1582-90.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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T1 - Circulating inhibitor of gonadotropin releasing hormone secretion by hypothalamic neurons in uremia
AU - Daschner, Markus
AU - Philippin, Bärbel
AU - Nguyen, Trang
AU - Wiesner, Rudolf J
AU - Walz, Claudia
AU - Oh, Jun
AU - Sandow, Jürgen
AU - Mehls, Otto
AU - Schaefer, Franz
PY - 2002/11
Y1 - 2002/11
N2 - BACKGROUND: Previous studies have suggested a neuroendocrine defect underlying uremic hypogonadism, characterized by a reduced secretion of gonadotropin-releasing hormone (GnRH) and luteinizing hormone (LH).METHODS: We studied the GnRH-producing GT1-7 cell line and the LH-producing LbetaT-2 pituitary cell line under uremic conditions to investigate whether substances circulating in uremic plasma directly affect hypothalamic or pituitary hormone secretion. The cells were incubated with serum from 5/6-nephrectomized or sham-nephrectomized castrated rats, respectively. Furthermore, GT1 cells were incubated with delipidated sera, serum subfractions separated by molecular weight, or several peptide hormones. Cellular viability, apoptosis rate and extracellular hormone degradation were assessed separately. GnRH and LH were measured by RIA in supernatants and cell lysates. GnRH gene expression was assessed by Northern blot.RESULTS: Uremic serum caused a reduction of extracellular GnRH concentration by 31%, whereas intracellular GnRH increased by 12%. This effect was independent of serum lipids and enzymatic GnRH degradation but was abolished by trypsin digestion. Cellular viability, apoptosis rates and GnRH gene expression did not differ between the two groups. The inhibitory activity was recovered from the high-molecular weight fraction, whereas the fraction <5 kD had stimulatory activity. In contrast, uremic serum did not affect LH secretion from LbetaT-2 cells, indicating that the hypoactivity of the hypothalamo-pituitary gonadotrope unit results from an inhibition at the hypothalamic rather than the pituitary level.CONCLUSIONS: Our results suggest that uremic serum contains macromolecular and hydrophilic peptide(s) able to specifically suppress the neurosecretion of GnRH from GT1-7 cells.
AB - BACKGROUND: Previous studies have suggested a neuroendocrine defect underlying uremic hypogonadism, characterized by a reduced secretion of gonadotropin-releasing hormone (GnRH) and luteinizing hormone (LH).METHODS: We studied the GnRH-producing GT1-7 cell line and the LH-producing LbetaT-2 pituitary cell line under uremic conditions to investigate whether substances circulating in uremic plasma directly affect hypothalamic or pituitary hormone secretion. The cells were incubated with serum from 5/6-nephrectomized or sham-nephrectomized castrated rats, respectively. Furthermore, GT1 cells were incubated with delipidated sera, serum subfractions separated by molecular weight, or several peptide hormones. Cellular viability, apoptosis rate and extracellular hormone degradation were assessed separately. GnRH and LH were measured by RIA in supernatants and cell lysates. GnRH gene expression was assessed by Northern blot.RESULTS: Uremic serum caused a reduction of extracellular GnRH concentration by 31%, whereas intracellular GnRH increased by 12%. This effect was independent of serum lipids and enzymatic GnRH degradation but was abolished by trypsin digestion. Cellular viability, apoptosis rates and GnRH gene expression did not differ between the two groups. The inhibitory activity was recovered from the high-molecular weight fraction, whereas the fraction <5 kD had stimulatory activity. In contrast, uremic serum did not affect LH secretion from LbetaT-2 cells, indicating that the hypoactivity of the hypothalamo-pituitary gonadotrope unit results from an inhibition at the hypothalamic rather than the pituitary level.CONCLUSIONS: Our results suggest that uremic serum contains macromolecular and hydrophilic peptide(s) able to specifically suppress the neurosecretion of GnRH from GT1-7 cells.
KW - Animals
KW - Blood Proteins/metabolism
KW - Cell Line
KW - Creatinine/blood
KW - Dose-Response Relationship, Drug
KW - Erythropoietin/pharmacology
KW - Gene Expression/physiology
KW - Gonadotropin-Releasing Hormone/genetics
KW - Growth Hormone/pharmacology
KW - Hot Temperature
KW - Hypothalamus/cytology
KW - Insulin-Like Growth Factor I/pharmacology
KW - Leptin/pharmacology
KW - Luteinizing Hormone/pharmacology
KW - Male
KW - Neurons/cytology
KW - Parathyroid Hormone/pharmacology
KW - Pituitary Gland/cytology
KW - Prolactin/pharmacology
KW - Rats
KW - Rats, Sprague-Dawley
KW - Urea/blood
KW - Uremia/metabolism
U2 - 10.1046/j.1523-1755.2002.00616.x
DO - 10.1046/j.1523-1755.2002.00616.x
M3 - SCORING: Journal article
C2 - 12371958
VL - 62
SP - 1582
EP - 1590
JO - KIDNEY INT
JF - KIDNEY INT
SN - 0085-2538
IS - 5
ER -
