|Reinhardt, Timothy - Tim|
Submitted to: Archives Of Biochemistry and Biophysics
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 5/30/1999
Publication Date: N/A
Citation: Interpretive Summary: Milk fever is a disease which affects 8-10% of the dairy cows in the US, which means that approximately 800,000 cows are affected each year. The combined direct and indirect costs of a milk episode are estimated to exceed $300 per cow. Our research groups' mission is to perform basic and applied research aimed at reducing these costs. This paper shows that 9-cis-retinoids (vitamin A compounds) and 1,25(OH)2D3 (active vitamin D) synergistically increase renal 24-hydroxylase activity. Presumably, this synergism is mediated through 9-cis-RA's interaction with its receptors. The precise mechanism for this synergism remains to be determined. The 9,13-di-cis-RA is an isomer that can be viewed as both at precursor of 9-cis-RA or an inactive breakdown product of 9-cis-RA in vivo. Thus, 1,25(OH)2D3's ability to increase 9,13-di-cis-RA's half-life in vivo further complicates the connections between vitamin D and vitamin A mediated gene regulation. This work is of importance because 9,13-di-cis-RA and 1,25(OH)2D3 are both elevated in the milk fever cow. Their potential interaction, which activates the 24-hydroxylase, could be detrimental to the milk fever cow as this enzyme inactivates a key hormone needed for the cow's recovery.
Technical Abstract: The RXR forms a heterodimer with the VDR to activate genes which are regulated by 1,25(OH)2D3. In the absence of RXR's ligand, 9-cis-RA, RXR appears to be a silent partner to VDR. The effect of 9-cis-RA on VDR/RXR heterodimer formation, and 1,25(OH)2D3-mediated gene expression in vivo remains unclear. We examined the effect of exogenous 9-cis-RA or 9-cis-RA precursors, 9,13-di-cis-RA and 9-cis-RCHO, on 1,25(OH)2D3 mediate induction rat renal 24-hydroxylase. The rats were treated as follows: 1) vehicle; 2) 1,25(OH)2D3; 3) 1,25(OH)2D3 + 9-cis-RA; 4) 1,25(OH)2D3 + 9,13-di-cis-RA; 5) 1,25(OH)2D3 + 9-cis-RCHO; 6) 9-cis-RA; 7) 9,13-di-cis- RA; and 8) 9-cis-RCHO. 1,25(OH)2D3 was administered IP 18 h prior to sacrifice. The retinoids were administered every 4 h, starting 28 h prior to sacrifice. The last retinoid dose was administered 4 h prior to sacrifice. Treatment with 1,25(OH)2D3 alone increased 24-hydroxylase from 35 +/- 6 (controls) to 258 +/- 44 pmol/min/g tissue. When 1,25(OH)2D3 was administered with 9-cis-RA, 9,13-di-cis-RA or 9-cis-RCHO, 24-hydroxylases were 568 +/- 56, 524 +/- 56, and 463 +/- 62 pmol/min/g tissue respectively. Furthermore, co-dosing of 1,25(OH)2D3 and 9-cis-retinoids resulted in higher circulating concentrations of 9-cis-RA, and 9,13-di-cis-RA when compared to rats dosed with 9-cis-retinoids alone. This was shown to be due to 1,25(OH)2D3 increasing the half-life of 9,13-di-cis-RA by 3-4 times. These results show that 9-cis-RA can act synergistically with 1,25(OH)2D3 in the regulation of 24-hydroxylase in vivo. Additionally, 1,25(OH)2D3 regulates 9,13-di-cis-RA metabolism in vivo.