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Background: Metabolic acidosis (MA) adversely affects protein and lipid metabolism as well as endocrine function. Adipose tissue communicates with the rest of the body through synthesis and release adipokines, such as leptin, adiponectin and TNF-alpha. Adiponectin enhances insulin sensitivity and possesses anti-atherogenic and anti-inflammatory properties. Circulating adiponectin correlates inversely with cardiovascular events. It is possible that MA negatively regulates adiponectin contributing to poor patient outcome. The present study investigates the effect of MA on adiponectin in vivo and in vitro., Methods: Twenty healthy female volunteers underwent a 7-day course of oral ammonium chloride (NH4Cl)-induced acidosis. Serum adiponectin was determined before and after NH4Cl ingestion. Adipocytes were differentiated from their precursors, human mesenchymal stem cells (hMSCs), in culture. Concentrated HCl was added to the media to lower pH. Adiponectin mRNA and protein were determined at 48 and 96 h by real-time RT-PCR and ELISA, respectively., Results: After a 7-day course of NH4Cl, serum bicarbonate decreased significantly associated with the increase in urine ammonium and titratable acid. Adiponectin decreased significantly from 10,623 to 9723 pg/mL (P<0.005). MA suppressed adiponectin mRNA in hMSC-derived adipocytes at 48 and 96 h (P<0.01). The amount of adiponectin released into the culture media declined corresponding to the mRNA levels (P<0.001). MA did not affect adipocyte triglyceride or protein content., Conclusions: MA lowered circulating adiponectin through inhibition of adiponectin gene transcription in adipocytes.

Background: Chronic metabolic acidosis (CMA) is known to induce renal phosphate wasting and hypophosphatemia by enhancing bone resorption and inhibiting renal phosphate reabsorption. However, nothing is known regarding changes in the plasma levels of phosphate-regulating hormones during CMA, especially in humans with normal kidney function., Methods: Fifteen healthy Thai female volunteers were given NH (4)Cl orally for 7 days to induce CMA with or without oral phosphate supplementation. Blood and 24-h urine specimens were collected prior to and after CMA induction. Plasma concentrations and fractional excretion of calcium and inorganic phosphate as well as plasma levels of fibroblast growth factor (FGF) 23, 25(OH)D (3), 1,25(OH) (2)D (3) and intact parathyroid hormone (iPTH) were determined., Results: CMA led to hypophosphatemia and hypocalcemia with increases in the fractional excretion of calcium and phosphate. Plasma concentrations of FGF23, 25(OH)D (3) and iPTH were decreased, whereas that of 1,25(OH) (2)D (3) was increased. After oral phosphate supplementation, CMA-induced changes in the concentrations of the studied ions, FGF23 and 25(OH)D (3), but not those of 1,25(OH) (2)D (3) and iPTH, were diminished., Conclusions: The CMA-induced hypophosphatemia was likely to initiate a negative feedback response, thereby leading to reduction in the plasma levels of hyperphosphaturic hormones, FGF23 and PTH. An increase in the plasma 1,25(OH) (2)D (3) level, despite diminishing 25(OH)D (3) storage pool, may help enhance the intestinal phosphate absorption. Oral phosphate supplementation abolished the effects of CMA on FGF23 and 25(OH)D (3) levels, suggesting that the plasma phosphate concentration is the primary regulator of the plasma levels of these hormones during CMA., (J. A. Barth Verlag in Georg Thieme Verlag KG Stuttgart. New York.)

Bone histology of distal renal tubular acidosis patients showed decreased bone formation with impaired bone matrix mineralization that is not entirely explained by an alteration in the mineral balance. Data from in vitro studies suggests a direct inhibitory effect of metabolic acidosis on osteoblast function. We investigated the effects of chronic metabolic acidosis on osteoblast differentiation from mesenchymal stem cells (MSCs). Human MSCs were allowed to differentiate into osteoblasts in culture. Concentrated hydrochloric acid was added to the medium to lower the bicarbonate concentration and pH. The expression of various osteoblastic genes and proteins and bone matrix mineralization were examined. Chronic metabolic acidosis enhanced the messenger RNA (mRNA) and protein expression of early osteoblast transcription factor, runx-2, whereas inhibiting osterix and having no effect on ATF-4. The expression of type I collagen, the most abundant bone matrix protein, was increased following the same pattern of runx-2. Likewise, metabolic acidosis slightly enhanced the expression of mature osteoblastic gene, osteocalcin. Study on mineralization revealed suppressed alkaline phosphatase mRNA and enzyme activity. Despite the augmented collagen deposit in acidic culture, bone matrix mineralization was impaired. In conclusion, chronic metabolic acidosis alters osteoblast differentiation from MSCs through its diverse effect on osteoblastic genes and proteins resulting in an impairment of bone formation.Kidney International (2007) 71, 201–209. doi:10.1038/sj.ki.5002035; published online 20 December 2006 [ABSTRACT FROM AUTHOR]