The GH/IGF1 axis in the kidney of young goats fed a protein-reduced diet.

Feeding approaches for ruminants are changing to reduce N excretion as a major source of pollution. Based on the ruminohepatic cycle of N, it was assumed that the metabolism of ruminants could tolerate a reduced-protein diet well. However, metabolic changes such as a reduction in hepatic IGF1 mRNA expression, resulting in lower blood IGF1 levels due to decreased hepatic growth hormone receptor (GHR) expression, were found. Therefore, the aim of the present study was to determine the effect of a low-protein diet on the expression of GHR and subsequent IGF1 signalling in the renal cortex of young male goats to verify whether organ-specific synthesis of IGF1 mRNA expression occurs. Kidney cortex samples were obtained from eight goats fed a control diet (20% CP) and nine animals fed a reduced-protein diet (9% CP). The expression of GHR in the kidneys was reduced, whereas the expression of Janus kinase 2 (JAK2), suppressor of cytokine signalling 3 and signal transducers and activators of transcription 3 (STAT3) increased significantly. The stimulated JAK2 expression could modulate the expression of STAT3, which led to increased renal IGF1 mRNA expression. These results suggest that this increase in IGF1 mRNA expression in the kidneys is tissue-specific. This could be due to the autocrine/paracrine IGF1 effect on renal cell metabolism during a protein-reduced diet. These signalling pathways need further investigation to understand how and why low levels of protein stimulate IGF1 synthesis differently in the kidney than in the liver.

Effects of diets differing in dietary cation-anion difference and calcium concentration on calcium homeostasis in neutered male sheep.

Feeding low dietary cation-anion difference (DCAD) diets is one strategy to prevent milk fever in cows. The mechanism of action, as well as whether the calcium (Ca) supply of such diets combined with this feeding regimen should meet the requirements, is still unclear. Small ruminants are commonly used as models for cows. The goal of the present study was to demonstrate basic effects of DCAD against a background of different Ca supplies in a sheep model. Twenty-three castrated male East Friesian milk sheep, aged 11 to 12 mo, were randomly assigned to 4 different feeding groups. The ration of each group was either high (highDCAD) or low in DCAD (lowDCAD) combined with adequate (nCa) or restricted Ca supply (lowCa). At baseline, serum and urine were collected from all sheep and a peripheral quantitative computed tomography of the left metatarsus was performed. After a 14-d adaptation period to the different diets, the experiment started (d 0). Urine, feces, and serum were collected on d 0, 4, 7, 14, and 22, and peripheral quantitative computed tomography was performed on d 0 and 22. On d 22, the sheep were killed and sampled for functional studies. LowDCAD was significantly associated with lower urine pH, higher urinary Ca excretion, higher ionized Ca in blood, and higher serum Ca concentrations. Blood pH and bone parameters did not differ significantly between groups. It is unclear from which compartment the high amounts of Ca excreted with urine in the lowDCAD groups originated. Interestingly, lowDCAD resulted in higher renal mRNA abundance of parathyroid hormone receptor but unaffected mRNA abundance of Ca transporters. As neither renal abundance of these transporters nor Ca excretion were influenced by dietary Ca supply, our results support the hypothesis that increased urinary Ca observed with low DCAD diets represents a loss rather than an excretion of surplus Ca.

Influence of 25-hydroxyvitamin D3 and 1,25-dihydroxyvitamin D3 on expression of P-glycoprotein and cytochrome P450 3A in sheep.

In order to improve calcium and phosphorus balance, beef cattle and dairy cows can be supplemented with vitamin D. However, different vitamin D metabolites have been shown to increase expression of P-glycoprotein (P-gp, MDR1, ABCB1) and cytochrome P450 3A (CYP3A) in rodents as well as in cell culture systems. As such interferences might have an impact on pharmacokinetics of some drugs widely-used in veterinary medicine, we investigated the expression of P-gp, CYP3A, vitamin D receptor (VDR), pregnane X receptor (PXR) and retinoid X receptor α (RXRα) in sheep either treated orally with 6µg/kg body weight (BW) 25-hydroxyvitamin D3 (OHD3) for ten days before sacrifice or 12h after intravenous injection of 0.5µg/kg BW 1,25-dihydroxyvitamin D3 (1,25- (OH)2D3). Down-regulation of ruminal, jejunal and hepatic, but not renal P-gp could be found with 25-OHD3 supplementation. Interestingly, this effect on P-gp was not observed in tissues from 1,25-(OH)2D3-treated sheep. In contrast, 1,25-(OH)2D3 induced a significant up-regulation of renal and jejunal CYP3A expression, while 25-OHD3 had no impact. Renal expression of VDR and PXR was also increased by treatment with 1,25-(OH)2D3, while jejunal PXR expression was only stimulated in sheep supplemented with 25-OHD3. Either treatments increased renal, but not ruminal, jejunal or hepatic expression of RXRα. These results demonstrate that the impact of large doses of vitamin D metabolites on different target organs and potential interactions with other medications should be further investigated in vitro and in vivo to understand the effects of vitamin D metabolites on metabolism and excretion pathways in livestock.