Physiological regulation of phosphate by vitamin D, parathyroid hormone (PTH) and phosphate (Pi)

Inorganic phosphate (Pi) is an abundant element in the body and is essential for a wide variety of key biological processes. It plays an essential role in cellular energy metabolism and cell signalling, e.g. adenosine and guanosine triphosphates (ATP, GTP), and in the composition of phospholipid membranes and bone, and is an integral part of DNA and RNA. It is an important buffer in blood and urine and contributes to normal acid-base balance. Given its widespread role in almost every molecular and cellular function, changes in serum Pi levels and balance can have important and untoward effects. Pi homoeostasis is maintained by a counterbalance between dietary Pi absorption by the gut, mobilisation from bone and renal excretion. Approximately 85% of total body Pi is present in bone and only 1% is present as free Pi in extracellular fluids. In humans, extracellular concentrations of inorganic Pi vary between 0.8 and 1.2 mM, and in plasma or serum Pi exists in both its monovalent and divalent forms (H2PO4- and HPO42-). In the intestine, approximately 30% of Pi absorption is vitamin D regulated and dependent. To help maintain Pi balance, reabsorption of filtered Pi along the renal proximal tubule (PT) is via the NaPi-IIa and NaPi-IIc Na+-coupled Pi cotransporters, with a smaller contribution from the PiT-2 transporters. Endocrine factors, including, vitamin D and parathyroid hormone (PTH), as well as newer factors such as fibroblast growth factor (FGF)-23 and its coreceptor α-klotho, are intimately involved in the control of Pi homeostasis. A tight regulation of Pi is critical, since hyperphosphataemia is associated with increased cardiovascular morbidity in chronic kidney disease (CKD) and hypophosphataemia with rickets and growth retardation. This short review considers the control of Pi balance by vitamin D, PTH and Pi itself, with an emphasis on the insights gained from human genetic disorders and genetically modified mouse models

Combined Effect of Dietary Cadmium and Benzo(a)pyrene on Metallothionein Induction and Apoptosis in the Liver and Kidneys of Bank Voles

Bank voles free living in a contaminated environment have been shown to be more sensitive to cadmium (Cd) toxicity than the rodents exposed to Cd under laboratory conditions. The objective of this study was to find out whether benzo(a)pyrene (BaP), a common environmental co-contaminant, increases Cd toxicity through inhibition of metallothionein (MT) synthesis—a low molecular weight protein that is considered to be primary intracellular component of the protective mechanism. For 6 weeks, the female bank voles were provided with diet containing Cd [less than 0.1 μg/g (control) and 60 μg/g dry wt.] and BaP (0, 5, and 10 μg/g dry wt.) alone or in combination. At the end of exposure period, apoptosis and analyses of MT, Cd, and zinc (Zn) in the liver and kidneys were carried out. Dietary BaP 5 μg/g did not affect but BaP 10 μg/g potentiated rather than inhibited induction of hepatic and renal MT by Cd, and diminished Cd-induced apoptosis in both organs. The hepatic and renal Zn followed a pattern similar to that of MT, attaining the highest level in the Cd + BaP 10-μg/g group. These data indicate that dietary BaP attenuates rather than exacerbates Cd toxicity in bank voles, probably by potentiating MT synthesis and increasing Zn concentration in the liver and kidneys

Još o toksičnosti kadmija - s posebnim osvrtom na nastanak oksidacijskoga stresa i na interakcije s cinkom i magnezijem

Discovered in late 1817, cadmium is currently one of the most important occupational and environmental pollutants. It is associated with renal, neurological, skeletal and other toxic effects, including reproductive toxicity, genotoxicity, and carcinogenicity. There is still much to find out about its mechanisms of action, biomarkers of critical effects, and ways to reduce health risks. At present, there is no clinically efficient agent to treat cadmium poisoning due to predominantly intracellular location of cadmium ions. This article gives a brief review of cadmium-induced oxidative stress and its interactions with essential elements zinc and magnesium as relevant mechanisms of cadmium toxicity. It draws on available literature data and our own results, which indicate that dietary supplementation of either essential element has beneficial effect under condition of cadmium exposure. We have also tackled the reasons why magnesium addition prevails over zinc and discussed the protective role of magnesium during cadmium exposure. These findings could help to solve the problem of prophylaxis and therapy of increased cadmium body burden.Iako je otkriven tek 1817. godine, kadmij je trenutačno jedan od najvažnijih onečišćivača životne i radne sredine. Štetno djeluje na bubrege, živčani sustav, kosti, reproduktivni sistem, a ima i genotoksične i karcinogene efekte. Nužna su dalja istraživanja vezana za mehanizme njegove toksičnosti, biomarkere efekata, kao i načine smanjenja rizika za zdravlje. Osim toga, do danas nije otkriven agens efikasan u terapiji trovanja kadmijem s obzirom na to da je kadmij intracelularni kation. U ovom radu dan je sažet pregled važnih mehanizama toksičnosti kadmija, kao što su nastanak oksidativnog stresa i interakcije s esencijalnim elementima, cinkom i magnezijem, na osnovi dostupnih literaturnih podataka, kao i naših ispitivanja koja upućuju na to da povećani unos navedenih esencijalnih elemenata pokazuje pozitivne efekte pri ekspoziciji kadmiju. Obrazložena je prednost suplementacije magnezijem pred suplementacijom cinkom i razmatrana preventivna uloga magnezija pri intoksikaciji kadmijem. Ovi su rezultati doprinos rješavanju problema profi lakse i terapije trovanja kadmijem

Urinary vesicles: in splendid isolation

Urine provides an attractive, non-invasive alternative to tissue, blood or other biofluid as a potential source of biomarkers of systemic and renal disease. The urinary protein content can be divided in two parts: soluble and solid-phase components; the solid-phase components can be subdivided into sediment preci-pitated with low-speed centrifugation and low-density nan-ometer-sized particles (vesicles <100 nm in diameter) precipitated by ultracentrifugation. In normal human adult urine, 48 % of the total urinary protein excreted is contained in the sediment, 49 % is soluble and the remaining 3 % is in urinary vesicles [1]. Pisitkun et al. [2] were the first to describe these vesicles in human urine and called them ‘exosomes’; they went on to demonstrate the potential for exosomes as a starting material for biomarker discovery in urine. They chose the term exosomes because the vesicles originate from the membranes o

Protease stimulation of renal sodium reabsorption in vivo by activation of the collecting duct epithelial sodium channel (ENaC)

Background: Proteases can increase the activity of the epithelial sodium channel (ENaC) by cleaving its α- or γ-subunit. However, evidence so far comes only from studies in vitro in either heterologous expression systems or isolated nephron segments. The present study has tested whether exposure to a luminal protease can alter sodium reabsorption along the rat collecting duct in vivo. Methods: Rats on normal laboratory chow were prepared for renal micropuncture. Late distal tubules of superficial nephrons were microinjected and perfused twice (3 nL min−1 for 3–6 min) with a solution similar to native tubular fluid, but containing 14[C]inulin and 22Na. The first perfusion was either a control solution or solution containing amiloride 1 mM or hydrochlorothiazide (HCTZ ) 1 mM; the second perfusion was either a control solution (time control) or a solution containing chymotrypsin 2 µg mL−1 ± aprotinin 100 µg mL−1 or amiloride 1 mM or HCTZ 1 mM. Urinary recoveries of 14[C]inulin and 22Na were recorded. Results: In time controls, the Na/In ratio did not change significantly (32.2 ± 3.4% versus 34.5 ± 3.1%). In contrast, chymotrypsin reduced the ratio from 33.3 ± 3.8% to 25.5 ± 2.5% (P < 0.05), indicating an increase in sodium reabsorption. When co-injected with chymotrypsin, the protease inhibitor aprotinin abolished the stimulatory effect of chymotrypsin on sodium reabsorption (31.7 ± 3.4% versus 32.1 ± 2.1%), while aprotinin alone had no effect. When chymotrypsin was co-injected with HCTZ, the Na/In ratio decreased from 36.8 ± 2.3% to 28.0 ± 3.4% (P < 0.05), whereas when given with amiloride, there was no change in the ratio (45.8 ± 3.4% versus 45.5 ± 2.3%), indicating that stimulation of sodium reabsorption by chymotrypsin was ENaC-dependent. Conclusions: These findings demonstrate proteolytic activation of ENaC in vivo, and suggest that changes in protease activity of the glomerular filtrate and tubular fluid in health or disease could affect net renal sodium excretion