Effects of growth hormone treatment on the pituitary expression of GHRH receptor mRNA in uremic rats.

BACKGROUND: A decreased ability of pituitary cells to secrete growth hormone (GH) in response to growth hormone releasing hormone (GHRH) stimulation has been shown in young uremic rats. The aim of the current study was to examine the effect of uremia and GH treatment on pituitary GHRH receptor expression. METHODS: Pituitary GHRH receptor mRNA levels were analyzed by RNase protection assay in young female rats made uremic by subtotal nephrectomy, either untreated (UREM) or treated with 10 IU/kg/day of GH (UREM-GH), and normal renal function animals fed ad libitum (SAL) or pair-fed with the UREM group (SPF). Rats were sacrificed 14 days after the second stage nephrectomy. RESULTS: Renal failure was confirmed by concentrations (X +/- SEM) of serum urea nitrogen (mmol/L) and creatinine (micromol/L) in UREM (20 +/- 1 and 89.4 +/- 4.5) and UREM-GH (16 +/- 1 and 91.4 +/- 6.9) that were much higher (P < 0.001) than those of sham animals (SAL, 3 +/- 0 and 26.5 +/- 2.2; SPF, 4 +/- 0 and 26.5 +/- 2.1). UREM rats became growth retarded as shown by a daily longitudinal tibia growth rate below (P < 0.05) that observed in SAL animals (156 +/- 3 vs. 220 +/- 5 microm/day). GH treatment resulted in significant growth rate acceleration (213 +/- 6 microm/day). GHRH receptor mRNA levels were no different among the SAL (0.43 +/- 0.03), SPF (0.43 +/- 0.08) and UREM (0.44 +/- 0.04) groups, whereas UREM-GH rats had significantly higher values (0.72 +/- 0.07). CONCLUSIONS: The status of pituitary GHRH receptor is not modified by nutritional deficit or by severe uremia causing growth retardation. By contrast, the growth promoting effect of GH administration is associated with stimulated GHRH receptor gene expression.

Exacerbated inflammatory response induced by insulin-like growth factor I treatment in rats with ischemic acute renal failure.

In agreement with recent studies showing a deleterious effect of growth hormone treatment in critically ill patients, preliminary data showed that insulin-like growth factor I (IGF-I) administration increased the mortality rate of rats with ischemic acute renal failure (ARF). The present study was designed to investigate the mechanism responsible for this unexpected effect. Male rats with ischemic ARF were given subcutaneous IGF-I, 50 microg/100 g at 0, 8, and 16 h after reperfusion (ARF+IGF-I, n = 5) or were untreated (ARF, n = 5). A group of 5 sham-operated rats were used as controls. Rats were killed 48 h after declamping, and the following studies were performed: in serum, creatinine and urea nitrogen; and in kidneys, histologic damage score, cellular proliferation by bromodeoxyuridine labeling, apoptosis by morphologic criteria, macrophage infiltration by immunohistochemistry using a specific antibody against ED-1, neutrophil infiltration by naphthol AS-D chloroacetate esterase staining, and levels of IGF-I and IGF-I receptor mRNA by RNase protection assay. ARF and ARF+IGF-I groups had a severe and similar degree of renal failure. Kidney damage was histologically more evident in ARF+IGF-I (1.9 +/- 0.1) than in ARF (1.3 +/- 0.2) rats, and the number of neutrophils/mm(2) of tissue was significantly greater in ARF+IGF-I than in ARF rats at the corticomedullary junction (52.3 +/- 5.2 versus 37.2 +/- 4.1) as well as at the renal medulla (172.5 +/- 30.0 versus 42.1 +/- 9.6). No other differences between the groups were found. It is concluded that IGF-I treatment enhanced the inflammatory response in rats with ischemic ARF. Cell toxicity derived from increased neutrophil accumulation might play a key role in the greater mortality risk of critically ill patients that are treated with growth hormone.

Histologic and dynamic changes induced by chronic metabolic acidosis in the rat growth plate.

To understand better the pathophysiology of growth impairment in persistent metabolic acidosis, the morphology and dynamics of the growth plate were studied in young rats grouped as follows: rats that were made acidotic by oral administration of ammonium chloride for 14 d (AC), nonacidotic rats that were fed ad libitum (control [C]), and nonacidotic rats that were pair-fed with the AC group (PF). AC rats became markedly acidotic and growth retarded. The volume of newly formed bone per day (mean +/- SEM) was significantly lowered (P < 0.05) in AC rats (AC, 3.4 +/- 0.4; C, 8.4 +/- 0.6; PF, 6.4 +/- 0.5 mm(3)/d). Growth plate height was lower in AC rats (303.8 +/- 12.7 microm) than in either C (478.0 +/- 16.0 microm) or PF rats (439.0 +/- 21.4 microm). The processes of chondrocyte proliferation (assessed by bromodeoxyuridine labeling) and maturation (assessed by stereologic estimators of size and shape of chondrocytes and the volume of matrix per cell) were not impaired by acidosis. By contrast, the dynamics of hypertrophic chondrocytes were altered significantly: both cell turnover per column per day (AC, 4.4 +/- 0.4; C, 8.0 +/- 0.8; PF, 6.2 +/- 0.6) and linear velocity of advance of chondrocytes (AC, 5.7 +/- 0.5; C, 11.2 +/- 0.9; PF, 9.4 +/- 0.8 microm/h) were lowered significantly. The study presented here shows the inhibitory effect of metabolic acidosis on cartilage cell progression and endochondral bone formation. Finally, the data show that metabolic acidosis caused a marked shortening of the growth plate because chondrocyte turnover was affected to a greater extent than bone tissue formation.