Tumor necrosis factor stimulates fibroblast growth factor 23 levels in chronic kidney disease and non-renal inflammation.

Fibroblast growth factor 23 (FGF23) regulates phosphate homeostasis, and its early rise in patients with chronic kidney disease is independently associated with all-cause mortality. Since inflammation is characteristic of chronic kidney disease and associates with increased plasma FGF23 we examined whether inflammation directly stimulates FGF23. In a population-based cohort, plasma tumor necrosis factor (TNF) was the only inflammatory cytokine that independently and positively correlated with plasma FGF23. Mouse models of chronic kidney disease showed signs of renal inflammation, renal FGF23 expression and elevated systemic FGF23 levels. Renal FGF23 expression coincided with expression of the orphan nuclear receptor Nurr1 regulating FGF23 in other organs. Antibody-mediated neutralization of TNF normalized plasma FGF23 and suppressed ectopic renal Fgf23 expression. Conversely, TNF administration to control mice increased plasma FGF23 without altering plasma phosphate. Moreover, in Il10-deficient mice with inflammatory bowel disease and normal kidney function, plasma FGF23 was elevated and normalized upon TNF neutralization. Thus, the inflammatory cytokine TNF contributes to elevated systemic FGF23 levels and also triggers ectopic renal Fgf23 expression in animal models of chronic kidney disease.

Cisplatin-induced injury of the renal distal convoluted tubule is associated with hypomagnesaemia in mice.

BACKGROUND: Cisplatin is an effective anti-neoplastic drug, but its clinical use is limited due to dose-dependent nephrotoxicity. The majority of cisplatin-treated patients develop hypomagnesaemia, often associated with a reduced glomerular filtration rate (GFR), polyuria and other electrolyte disturbances. The aim of this study is to unravel the molecular mechanism responsible for these particular electrolyte disturbances. METHODS: Two groups of 10 mice were injected intraperitoneally three times, once every 4 days, with cisplatin (5 mg/kg body weight,) or vehicle. Serum and urine electrolyte concentrations were determined. Next, renal mRNA levels of distal convoluted tubule (DCT) genes epithelial Mg(2+) channel TRPM6, the Na(+)-Cl(-) cotransporter (NCC), and parvalbumin (PV), as well as marker genes for other tubular segments were measured by real-time qPCR. Subsequently, renal protein levels of NCC, PV, aquaporin 1 and aquaporin 2 were determined using immunoblotting and immunohistochemistry (IHC). RESULTS: The cisplatin-treated mice developed significant polyuria (2.5 ± 0.3 and 0.9 ± 0.1 mL/24 h, cisplatin versus control, P < 0.05), reduced creatinine clearance rate (CCr) (0.18 ± 0.02 and 0.26 ± 0.02 mL/min, cisplatin versus control, P < 0.05) and a substantially reduced serum level of Mg(2+) (1.23 ± 0.03 and 1.58 ± 0.03 mmol/L, cisplatin versus control, P < 0.05), whereas serum Ca(2+), Na(+) and K(+) values were not altered. Measurements of 24 h urinary excretion demonstrated markedly increased Mg(2+), Ca(2+), Na(+) and K(+) levels in the cisplatin-treated group, whereas Pi levels were not changed. The mRNA levels of TRPM6, NCC and PV were significantly reduced in the cisplatin group. The expression levels of the marker genes for other tubular segments were unaltered, except for claudin-16, which was significantly up-regulated by the cisplatin treatment. The observed DCT-specific down-regulation was confirmed at the protein level. CONCLUSIONS: The present study identified the DCT as an important cisplatin-affected renal segment, explaining the high prevalence of hypomagnesaemia following treatment.

MYCN haploinsufficiency is associated with reduced brain size and intestinal atresias in Feingold syndrome.

Feingold syndrome is characterized by variable combinations of esophageal and duodenal atresias, microcephaly, learning disability, syndactyly and cardiac defect. We show here that heterozygous mutations in the gene MYCN are present in Feingold syndrome. All mutations are predicted to disrupt both the full-length protein and a new shortened MYCN isoform, suggesting that multiple aspects of early embryogenesis and postnatal brain growth in humans are tightly regulated by MYCN dosage.