During chronic kidney disease (CKD), alterations in bone and mineral metabolism include increased production of the hormone fibroblast growth factor 23 (FGF23) that may contribute to cardiovascular mortality. The osteocyte protein dentin matrix protein 1 (DMP1) reduces FGF23 and enhances bone mineralization, but its effects in CKD are unknown. We tested the hypothesis that DMP1 supplementation in CKD would improve bone health, prevent FGF23 elevations and minimize consequent adverse cardiovascular outcomes. We investigated DMP1 regulation and effects in wild-type (WT) mice and the Col4a3 −/− mouse model of CKD. Col4a3 −/− mice demonstrated impaired kidney function, reduced bone DMP1 expression, reduced bone mass, altered osteocyte morphology and connectivity, increased osteocyte apoptosis, increased serum FGF23, hyperphosphatemia, left ventricular hypertrophy (LVH), and reduced survival. Genetic or pharmacological supplementation of DMP1 in Col4a3 −/− mice prevented osteocyte apoptosis, preserved osteocyte networks, corrected bone mass, partially lowered FGF23 levels by attenuating NFAT-induced FGF23 transcription, and further increased serum phosphate. Despite impaired kidney function and worsened hyperphosphatemia, DMP1 prevented development of LVH and improved Col4a3 −/− survival. Our data suggest that CKD reduces DMP1 expression, whereas its restoration represents a potential therapeutic approach to lower FGF23 and improve bone and cardiac health in CKD.

The bone-secreted hormone fibroblast growth factor 23 (FGF23) has an essential role in phosphate homeostasis by regulating expression of the kidney proximal tubule sodium-phosphate cotransporters as well as parathyroid hormone levels. Induction of FGF23 early in chronic kidney disease (CKD) helps to maintain normal phosphorous levels. However, high FGF23 levels become pathological as kidney disease progresses and are associated with an increased risk of CKD progression, cardiovascular events, and death. The factors responsible for increasing FGF23 levels early in CKD are unknown, but recent work has proposed a role for inflammation and disordered iron homeostasis. Notably, FGF23 has recently been shown to elicit an inflammatory response and to display immunomodulatory properties. Here, we will review emerging evidence on the cross talk between inflammation, iron, FGF23, and bone and mineral metabolism and discuss the relevance for CKD patients.

Purpose of review Fibroblast growth factor 23 (FGF23) is a hormone secreted by osteocytes and osteoblasts that regulates phosphorus and vitamin D homeostasis. FGF23 levels increase progressively in chronic kidney disease (CKD), and FGF23 excess might be a causal factor of left ventricular hypertrophy, CKD progression and death. Therefore, understanding the molecular mechanisms that control FGF23 production is a critical to design therapies to lower FGF23 levels. The present review focuses on the role of inflammatory stimuli on FGF23 regulation and summarizes recent studies that support a novel framework linking inflammation to FGF23 regulation. Recent findings Inflammation and iron deficiency, which are common occurrences in CKD have emerged as novel FGF23 regulators. Recent findings show that inflammation increases FGF23 production in bone through direct and iron-related indirect mechanisms. In these settings, Hypoxia Inducible Factor (HIF)-1α orchestrates FGF23 transcription in response to inflammation and is primarily responsible for coordinating FGF23 production and cleavage. Summary We demonstrate that inflammation increases FGF23 production and may contribute to elevated FGF23 levels in CKD. Osseous HIF-1α may represent a therapeutic target to lower FGF23 levels in CKD patients and minimize the negative consequences associated with FGF23 excess.

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Five ileal-cannulated adult dogs were utilized in a 5 x 5 Latin square design to determine the effects of fructan type and concentration on nutrient digestibility, stool metabolite concentrations, and fecal microbiota. Five diets were evaluated that contained cellulose alone or with inulin or short-chain fructooligosaccharides (scFOS) each at 0.2 or 0.4% of the diet. Dogs were fed 175 g of their assigned diet twice daily. Chromic oxide served as a digestibility marker. Nutrient digestibility; ileal and fecal pH and ammonia concentrations; ileal IgA concentrations; and fecal short- and branched-chain fatty acid concentrations, microbiota, and concentrations of phenol, indole, and biogenic amines were measured. No differences were observed in ileal pH or ammonia or fecal concentrations of indole or valerate. Ileal DM, OM, and CP digestibility coefficients; total tract DM and OM digestibility coefficients; and fecal concentrations of phenylethylamine increased linearly (P < 0.05), and fecal concentrations of phenol decreased linearly (P < 0.05) with inulin supplementation. Fecal concentrations of acetate, propionate, and total short-chain fatty acids decreased quadratically (P < 0.05) with inulin supplementation. Ileal DM, OM, and CP digestibility coefficients increased linearly (P < 0.05), and fecal phenol concentration decreased linearly (P < 0.05) with scFOS supplementation. Total tract DM and OM digestibility coefficients as well as fecal butyrate and isobutyrate concentrations increased quadratically (P < 0.05) with scFOS supplementation. Although a greater level of inclusion is needed to modify gut microbiota populations, low-level inclusion of inulin or scFOS is effective in modifying key nutritional outcomes in the dog.

In conclusion, B6-Col4a3KO mice manifest slower CKD progression and longer survival than 129Sv-Col4a3KO mice and can serve as a novel model of cardiorenal disease.

The isoflavone content of 46 subterranean clover varieties was estimated by a microtechnique which allowed of the semiquantitative analysis of 100 leaf samples per day. The relative proportions of the three major isoflavones varied greatly between varieties. Twenty-four of the varieties tested were low in formononetin. When crushed leaf blade samples were allowed to stand prior to the addition of ethanol there was a decline in detectable genistein. The rate of decline was dependent on the temperature during standing.

Flooding the roots of T. subterraneum grown in sand culture induced large (often 30-fold) increases in alcohol dehydrogenase (ADH) activity, indicative of anaerobic respiration. In pot culture the levels of ADH activity were lower in varieties of subspecies yanninicum than in varieties of subspecies brachycalycinum and subterraneum. The varieties took 6–9 days to reach maximum ADH values, indicating a flooding period of this order is suitable in varietal testing for flooding tolerance. Lower ADH levels in subspecies yanninicum were not evident when the roots were tested after 3 days in anaerobic solution culture.