Cubilin maintains blood levels of HDL and albumin.

Cubilin is an endocytic receptor highly expressed in renal proximal tubules, where it mediates uptake of albumin and filtered forms of apoA-I/HDL. Cubilin deficiency leads to urinary loss of albumin and apoA-I; however, the consequences of cubilin loss on the homeostasis of blood albumin and apoA-I/HDL have not been studied. Using mice heterozygous for cubilin gene deletion (cubilin HT mice), we show that cubilin haploinsufficiency leads to reduced renal proximal tubular uptake of albumin and apoA-I and significantly increased urinary loss of albumin and apoA-I. Moreover, cubilin HT mice displayed significantly decreased blood levels of albumin, apoA-I, and HDL. The levels of albumin and apoA-I protein or mRNA expressed in the liver, kidney, or intestine of cubilin HT mice did not change significantly. The clearance rate of small HDL3 particles (density>1.13 g/ml) from the blood increased significantly in cubilin HT mice. In contrast, the rate of clearance of larger HDL2 particles from the blood did not change significantly, indicating a decreased half-life for HDL particles capable of filtering through the glomerulus. On the basis of these findings, we conclude that cubilin deficiency reduces renal salvage and delivery back to the blood of albumin and apoA-I, which decreases blood levels of albumin and apoA-I/HDL. These findings raise the possibility that therapeutic increase of renal cubilin expression might reduce proteinuria and increase blood levels of albumin and HDL.

Cubilin expression is monoallelic and epigenetically augmented via PPARs.

BACKGROUND: Cubilin is an endocytic receptor that is necessary for renal and intestinal absorption of a range of ligands. Endocytosis mediated by cubilin and its co-receptor megalin is the principal mechanism for proximal tubule reabsorption of proteins from the glomerular filtrate. Cubilin is also required for intestinal endocytosis of intrinsic factor-vitamin B12 complex. Despite its importance, little is known about the regulation of cubilin expression. RESULTS: Here we show that cubilin expression is under epigenetic regulation by at least two processes. The first process involves inactivation of expression of one of the cubilin alleles. This monoallelic expression state could not be transformed to biallelic by inhibiting DNA methylation or histone deacetylation. The second process involves transcriptional regulation of cubilin by peroxisome proliferator-activated receptor (PPAR) transcription factors that are themselves regulated by DNA methylation and histone deacetylation. This is supported by findings that inhibitors of DNA methylation and histone deacetylation, 5Aza and TSA, increase cubilin mRNA and protein in renal and intestinal cell lines. Not only was the expression of PPARα and γ inducible by 5Aza and TSA, but the positive effects of TSA and 5Aza on cubilin expression were also dependent on both increased PPAR transcription and activation. Additionally, 5Aza and TSA had similar effects on the expression of the cubilin co-receptor, megalin. CONCLUSIONS: Together, these findings reveal that cubilin and megalin mRNA expression is under epigenetic control and thus point to new avenues for overcoming pathological suppression of these genes through targeting of epigenetic regulatory processes.

Social interactions tune aggression and stress responsiveness in a territorial cichlid fish (Archocentrus nigrofasciatus).

We examined the relative influences of pre-fight housing condition, contest intensity, and contest outcome in modulating post-fight stress hormone concentrations in territorial male convict cichlids (Archocentrus nigrofasciatus). Individuals were housed either in isolation or in semi-natural communal tanks. Pairs of male cichlids that differed considerably in body mass were selected from the same housing regime. Pre-fight water-borne cortisol levels were obtained before allowing the dyad to interact until contest resolution, after which time post-fight cortisol levels were obtained from the winner and loser. There were no outcome-related differences in post-fight cortisol concentrations following escalated or non-escalated contests, a result that held true for both housing regimes. Pre-fight cortisol levels were significantly higher than post-fight cortisol levels, suggesting that initial confinement in a beaker for the water-borne hormone samples was a stressor, but that the animals acclimated quickly to confinement. Fights involving previously isolated participants were significantly more intense than those involving group-housed animals, which we explain as being a function of established relationships between social isolation, heightened acute cortisol responsiveness, and the expression of excessive aggressive behavior. Only group-housed losers demonstrated the ability to modulate aggression or hypothalamic-pituitary-interrenal (HPI) activity in a graded fashion to acute increases in cortisol or changes in contest intensity, respectively. We discuss a variety of factors that could disrupt the ability of isolates to appropriately modulate interactions between social behavior and the HPI axis, and we examine a number of functional hypotheses underlying the sensitivity of group-housed losers to changes in contest dynamics.