Growth Hormone Secretory Capacity of Individual Somatotropes in Rats with Chronic Renal Insufficiency

Poletti, Lawrence F.; Krieg, Richard J.; Santos, Fernando; Niimi, Kazuhiko; Hanna, James D.; Chan, James C.M.

doi:10.1203/00006450-199205000-00025

Cited by 10 publications

(13 citation statements)

References 15 publications

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“…Recent studies in the uremic rat model have sought to identify the molecular mechanisms that alter the neuroendocrine control of GH secretion in renal failure. Isolated somatotropes from rats with preterminal CRF retained normal responsiveness to GHRH in vitro indicating that the hypothalamus, rather than the pituitary gland, is the major site of dysregulation of GH secretion in uremia (45). In the hypothalamus, lower GHRH mRNA concentrations and an unchanged hypothalamic somatostatin mRNA content were found in uremic animals (46).…”

Section: Discussionmentioning

confidence: 84%

Deconvolution Analysis of Spontaneous Nocturnal Growth Hormone Secretion in Prepubertal Children with Preterminal Chronic Renal Failure and with End-Stage Renal Disease

et al. 1995

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We sought to determine whether elevated circulating growth hormone (GH) concentrations in uremic prepubertal children are due to an increase in GH secretory activity by the pituitary gland or a decrease in the metabolic clearance of GH consequent to reduced GFR. Deconvolution analysis was applied to the nighttime plasma GH profiles of 1 ) 11 children with preterminal chronic renal failure, 2) 12 children with end-stage renal disease (ESRD), and 3) a control group of matched children with idiopathic short stature (n = 12). Mean (t SEM) half-life of endogenous GH in children with ESRD (27.5 ? 2.7 min) and preterminal chronic renal failure (23.1 ? 2.1 min) was significantly higher than in controls (14.8 ? 1.6 min; p < 0.001). GH half-life correlated inversely with GFR (r = -0.65, p < 0.001).The number of GH secretory bursts110 h in ESRD (8.1 ? 0.4) was amplified compared with preterminal chronic renal failure (6.4 2 0.5) and with controls (5.9 ? 0.4; p < 0.005). GH production rate varied over a broad range in the three groups: It was highest in ESRD (202 ? 56.6 mg/L/10 h; range 36-683), mainly as a result of an increased number of GH secretory bursts, and not statistically different in preterminal chronic renal failure (66.2 ? 11.4 mg/L/lO h; range 25-168) and in controls (129 ? 27.7 mg/L/10 h; range 39-392). Increased GH half-life, in concert with an increased GH production in some individuals with ESRD, leads to a 2.5-fold increase in the mean plasma GH concentration in ESRD compared with the two other groups ( p < 0.005). However, total immunoreactive plasma IGF-I levels were indistinguishable between groups. This disruption of the normal relationship between circulating GH and total plasma IGF-I levels in ESRD suggests a relative insensitivity to the action of GH in uremia, at least in those target organs (e.g. liver) that contribute predominantly to circulating IGF-I levels. regulation of the frequency and amplitude of pulsatile GH secretion, cannot be quantitated accurately in single blood determinations. Measurements of pulsatile plasma GH concentrations have been performed in prepubertal (4) and pubertal (5) children with CRF. Unfortunately, both studies lacked suitable control groups and did not provide insights into neurosecretory events and concurrent hormone clearance that together underlie the plasma GH pulse patterns. Such information is important particularly in patients with CRF, because the kidney is believed to account for a substantial fraction of the total plasma turnover of GH in humans (25-53%) (6) and in rats (67%) (7). Thus, in children with CRF, the question remains unresolved whether increased plasma GH concentrations are primarily due to increased GH secretion or decreased GH elimination by the kidney.

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Section: Discussionmentioning

confidence: 84%

Deconvolution Analysis of Spontaneous Nocturnal Growth Hormone Secretion in Prepubertal Children with Preterminal Chronic Renal Failure and with End-Stage Renal Disease

et al. 1995

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“…This resulted in a 5/6 nephrectomized (NX) rat model [5,8,9,15,16]. Sham and pair-fed groups were established as previously described [5,8,9,15,16]. In all, there were four groups of animals: sham-operated control rats, sham-operated controls pair-fed to the NX rats, NX rats, and NX rats given GHS.…”

Section: Methodsmentioning

confidence: 99%

“…After a 6-day adaptation period, two groups of animals were subjected to a 2/3 nephrectomy of the left kidney, followed by a contralateral nephrectomy 1 week later. This resulted in a 5/6 nephrectomized (NX) rat model [5,8,9,15,16]. Sham and pair-fed groups were established as previously described [5,8,9,15,16].…”

Section: Methodsmentioning

confidence: 99%

“…The dose-related stimulation of GH secretion by GH-releasing hormone from dispersed pituitary cells in vitro is not decreased during uremia [15], nor is the secretory capacity of individual somatotropes [16]. Thus, the possibility arises that, during uremia, the pituitary gland might still be stimulated to secrete enough GH to restore growth.…”

Section: Introductionmentioning

confidence: 98%

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Growth hormone and growth hormone-related mRNA in uremic rats: effect of a growth hormone secretagogue

et al. 2002

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In experimental animals, the decreased growth during mild uremia is not accompanied by a loss in the capacity of the pituitary gland to secrete growth hormone (GH). With the development of orally administered GH "secretagogues" (GHS), it might be possible to stimulate growth during uremia without injections. This study was designed to determine the effects of the GHS, L-163,255. Uremia was induced by 5/6 nephrectomy (NX). GHS was given orally, 3 mg/kg, twice a week. Four groups of animals included: (1) sham-operated, (2) sham-operated, pair-fed, (3) uremic (NX), and (4) uremic, GHS-treated (NX+GHS). Blood sampling was conducted via intra-atrial catheters, and GH was quantitated. Pituitary GH mRNA was measured by Northern blot, and liver GH receptor and insulin-like growth factor-I mRNAs by RNAase protection. Untreated NX animals had a specific decrease in the "mass" of the GH pulses. A burst of GH was induced by GHS, but the pulsatile pattern of GH secretion over 6 h was not affected. An increase or a return to non-uremic levels of GH-related mRNAs occurred after GHS. Thus, GHS stimulated an acute burst of GH secretion and increased specific mRNAs encoding GH-related proteins in uremic animals.

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“…Deficient GH secretion is remarkable in view of diminished feedback inhibition predicted by low free IGF-1 and high IGFBP concentrations, resulting from additional defects of cellular GH signal transduction and IGFBP turnover in CRF [11,12,13]. In vitro studies show that somatotrope responsiveness to the principal hypothalamic agonist, GHRH, is preserved in the uremic rat [14]. Feedforward failure arises instead from impoverished GHRH output, reflected in decreased hypothalamic GHRH gene expression [15].…”

Section: Growth Hormonementioning

confidence: 97%

Neuroendocrine adaptations in renal disease

2003

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Chronic renal failure (CRF) disrupts the time-dependent secretion of multiple hormones. The present review focuses on altered pulsatile release of peptide hormones. CRF is marked by impaired tissue actions, disorderly release patterns, and relative [growth hormone (GH)] or absolute [luteinizing hormone (LH)] deficiency of secretion. At the hypothalamo-pituitary level, experimental evidence suggests that CRF reduces the synthesis and/or release of the cognate hypothalamic releasing factors, GHRH and LHRH, and enforces excessive inhibition by somatostatin. Parathyroid hormone (PTH) and insulin are secreted in both basal and pulsatile modes, wherein the latter is putatively coordinated by autonomic innervation. Amplitude and frequency-dependent adaptations of PTH and insulin outflow fail in CRF, as assessed under steady-state conditions and during metabolic drive (i.e., calcium for PTH and glucose for insulin). A common feature in CRF is a diminished mass of hormone released per burst, due in principle to attenuation of feedforward signals and/or accentuation of (unknown) feedback signals. Damping of neuronal control and/or prolonged network response times may contribute to aberrant pulse frequency, disproportionate basal (nonpulsatile) hormone release, and consistent erosion of secretory process regularity in the uremic state. The homeostatic consequences of distorted secretory dynamics, tissue resistance, impaired hormone clearance, and altered mean agonist concentrations are evident in certain therapeutic interventions, such as GH supplementation in CRF.

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Growth Hormone Secretory Capacity of Individual Somatotropes in Rats with Chronic Renal Insufficiency

Cited by 10 publications

References 15 publications

Deconvolution Analysis of Spontaneous Nocturnal Growth Hormone Secretion in Prepubertal Children with Preterminal Chronic Renal Failure and with End-Stage Renal Disease

Deconvolution Analysis of Spontaneous Nocturnal Growth Hormone Secretion in Prepubertal Children with Preterminal Chronic Renal Failure and with End-Stage Renal Disease

Growth hormone and growth hormone-related mRNA in uremic rats: effect of a growth hormone secretagogue

Neuroendocrine adaptations in renal disease

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