Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020438 (hypercalciuria)
 2,502 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

FK506 (tacrolimus) and dexamethasone are potent immunosuppressants known to induce significant side effects on mineral homeostasis, including hypercalciuria and hypomagnesemia. However, the underlying molecular mechanisms remain unknown. The present study investigated the effects of FK506 and dexamethasone on the expression of proteins involved in active Ca(2+) reabsorption: the epithelial Ca(2+) channel TRPV5 and the cytosolic Ca(2+)-binding protein calbindin-D(28K). In addition, the renal expression of the putative Mg(2+) channel TRPM6, suggested to be involved in transcellular Mg(2+) reabsorption, was determined. Administration of FK506 to rats by daily oral gavage during 7 d significantly enhanced the urinary excretion of Ca(2+) and Mg(2+) and induced a significant hypomagnesemia. FK506 significantly decreased the renal mRNA expression of TRPV5 (62 +/- 7% relative to controls), calbindin-D(28K) (9 +/- 1%), and TRPM6 (52 +/- 8%), as determined by real-time quantitative PCR analysis. Furthermore, semiquantitative immunohistochemistry showed reduced renal protein abundance of TRPV5 (24 +/- 5%) and calbindin-D(28K) (29 +/- 4%), altogether suggesting that downregulation of these transport proteins is responsible for the FK506-induced Ca(2+) and Mg(2+) wasting. In contrast, dexamethasone significantly enhanced renal TRPV5 (150 +/- 15%), calbindin-D(28K) (177 +/- 23%), and TRPM6 (156 +/- 20%) mRNA levels along with TRPV5 (211 +/- 8%) and calbindin-D(28K) (176 +/- 5%) protein abundance in the presence of significantly increased Ca(2+) and Mg(2+) excretion. This indicated that these proteins are directly or indirectly regulated by dexamethasone. In conclusion, FK506 and dexamethasone induce renal Ca(2+) and Mg(2+) wasting, albeit by different mechanisms. Downregulation of specific Ca(2+) and Mg(2+) transport proteins provides a molecular mechanism for FK506-induced hypercalciuria and hypomagnesemia, whereas dexamethasone positively regulates these proteins.
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PMID:Downregulation of Ca(2+) and Mg(2+) transport proteins in the kidney explains tacrolimus (FK506)-induced hypercalciuria and hypomagnesemia. 1497 56

Chronic metabolic acidosis results in renal Ca2+ and Mg2+ wasting, whereas chronic metabolic alkalosis is known to exert the reverse effects. It was hypothesized that these adaptations are mediated at least in part by the renal Ca2+ and Mg2+ transport proteins. The aim of this study, therefore, was to determine the effect of systemic acid-base status on renal expression of the epithelial Ca2+ channel TRPV5, the Ca2+-binding protein calbindin-D28K, and the epithelial Mg2+ channel TRPM6 in relation to Ca2+ and Mg2+ excretion. Chronic metabolic acidosis that was induced by NH4Cl loading or administration of the carbonic anhydrase inhibitor acetazolamide for 6 d enhanced calciuresis accompanied by decreased renal TRPV5 and calbindin-D28K mRNA and protein abundance in wild-type mice. In contrast, metabolic acidosis did not affect Ca2+ excretion in TRPV5 knockout (TRPV5-/-) mice, in which active Ca2+ reabsorption is effectively abolished. This demonstrates that downregulation of renal Ca2+ transport proteins is responsible for the hypercalciuria. Conversely, chronic metabolic alkalosis that was induced by NaHCO3 administration for 6 d increased the expression of Ca2+ transport proteins accompanied by diminished urine Ca2+ excretion in wild-type mice. However, this Ca2+-sparing action persisted in TRPV5-/- mice, suggesting that additional mechanisms apart from upregulation of active Ca2+ transport contribute to the hypocalciuria. Furthermore, chronic metabolic acidosis decreased renal TRPM6 expression, increased Mg2+ excretion, and decreased serum Mg2+ concentration, whereas chronic metabolic alkalosis resulted in the exact opposite effects. In conclusion, these data suggest that regulation of Ca2+ and Mg2+ transport proteins contributes importantly to the effects of acid-base status on renal divalent handling.
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PMID:Acid-base status determines the renal expression of Ca2+ and Mg2+ transport proteins. 1642 Dec 27

Diabetes is associated with renal calcium and magnesium wasting, but the molecular mechanisms of these defects are unknown. We measured renal calcium and magnesium handling and investigated the effects of diabetes on calcium and magnesium transporters in the thick ascending limb and distal convoluted tubule in streptozotocin (STZ)-induced diabetic rats. Rats were killed 2 weeks after inducing diabetes, gene expression of calcium and magnesium transporters in the kidney was determined by real-time polymerase chain reaction, and the abundance of protein was assessed by immunoblotting. Our results showed that diabetic rats had significant increase in the fractional excretion for calcium and magnesium (both P < 0.01), but not for sodium. Reverse transcriptase-polymerase chain reaction revealed significant increases in messenger RNA abundance of transient potential receptor (TRP) V5 (223 +/- 10%), TRPV6 (177 +/- 9%), calbindin-D28k (231 +/- 8%), and TRPM6 (165 +/- 8%) in diabetic rats. Sodium chloride cotransporter was also increased (207 +/- 10%). No change was found in paracellin-1 (cortex: 108 +/- 8%; medulla: 110 +/- 10%). Immunofluorescent studies of renal sections showed significant increase in calbindin-D28k (238 +/- 10%) and TRPV5 (211 +/- 10%), but no changes in paracellin-1 in Western blotting (cortex: 110 +/- 7%; medulla: 99 +/- 7%). Insulin administration completely corrected the hyperglycemia-associated hypercalciuria and hypermagnesiuria, and reversed the increase of calcium and magnesium transporter abundance. In conclusion, our results demonstrated increased renal calcium and magnesium transporter abundance in STZ-induced diabetic rats, which may represent a compensatory adaptation for the increased load of calcium and magnesium to the distal tubule.
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PMID:Increased renal calcium and magnesium transporter abundance in streptozotocin-induced diabetes mellitus. 1655 23

The transient receptor potential (TRP) superfamily consists, in mammals, of six protein subfamilies, TRPC, TRPM, TRPV, TRPA, TRPML and TRPP. TRPs are cation channels involved in many physiological processes and in the pathogenesis of various disorders. In the kidney, TRP channels are expressed along the nephron, and a role for some of these channels in renal function has been proposed. TRPC3 is thought to facilitate calcium ion influx into the principal cells of the collecting duct in response to vasopressin. TRPM3 and TRPV4 might be osmosensors, whereas the TRPP1/TRPP2 complex could function as a mechanosensor in the cilia of renal epithelial cells. A number of kidney diseases have also been linked to dysfunctional activity of TRPs. TRPC6 dysfunction has been associated with the onset of focal segmental glomerosclerosis; TRPP2 dysfunction is linked to autosomal-dominant polycystic kidney disease, TRPM6 mutations underlie hypomagnesemia with secondary hypocalcemia, and TRPV1 dysfunction is implicated in renal hypertension. A link between TRPC1 dysfunction and diabetic nephropathy has also been suggested in an animal model. Animal studies have implicated a role for TRPV5 in idiopathic hypercalciuria and vitamin D-dependent rickets, although these observations have not been confirmed in patients. This Review focuses on the role of renal TRP channels in health and disease.
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PMID:The role of transient receptor potential channels in kidney disease. 1954 62

The kidney plays an important role in maintaining the systemic Ca2+ and Mg2+ balance. Thus the renal reabsorptive capacity of these cations can be amended to adapt to disturbances in plasma Ca2+ and Mg2+ concentrations. The reabsorption of Ca2+ and Mg2+ is driven by transport of other electrolytes, sometimes through selective channels and often supported by hormonal stimuli. It is, therefore, not surprising that monogenic disorders affecting such renal processes may impose a shift in, or even completely blunt, the reabsorptive capacity of these divalent cations within the kidney. Accordingly, in Dent's disease, a disorder with defective proximal tubular transport, hypercalciuria is frequently observed. Dysfunctional thick ascending limb transport in Bartter's syndrome, familial hypomagnesaemia with hypercalciuria and nephrocalcinosis, and diseases associated with Ca2+-sensing receptor defects, markedly change tubular transport of Ca2+ and Mg2+. In the distal convolutions, several proteins involved in Mg2+ transport have been identified [TRPM6 (transient receptor potential melastatin 6), proEGF (pro-epidermal growth factor) and FXYD2 (Na+/K+-ATPase gamma-subunit)]. In addition, conditions such as Gitelman's syndrome, distal renal tubular acidosis and pseudohypoaldosteronism type II, as well as a mitochondrial defect associated with hypomagnesaemia, all change the renal handling of divalent cations. These hereditary disorders have, in many cases, substantially increased our understanding of the complex transport processes in the kidney and their contribution to the regulation of overall Ca2+ and Mg2+ balance.
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PMID:Hereditary tubular transport disorders: implications for renal handling of Ca2+ and Mg2+. 1978 Jul 17

The Drosophila trp homologue Transient Receptor Potential (TRP) cation channels are ubiquitous in most species and cell types. The functional TRP subclasses TRPC, TRPV and TRPP gate Ca2+ and other cations in mammalian tissues, including the kidney. It is now clear that TRP channels play an important role in renal physiology and in certain genetic disorders of the kidney. Hence, there is considerable interest in targeting mutated or dysfunctional TRP channels in an effort to treat such diseases. Transcellular epithelial cell Ca2+ reabsorption occurs in the distal tubule via luminal TRPV5/V6 channels. Indeed, TRPV5 KO mice display phenotypic defects of renal disease, including hypercalciuria and impaired bone mineral density. Similar to Ca2+, Mg2+ transcellular reabsorption occurs in the distal convoluted tubule via apical TRPM6/TRPM7 channels. TRPC6 is a component of the glomerular podocyte "slit diaphragm" and its autosomic dominant mutation has been linked to a familial, steroid-resistant form of nephrotic syndrome. A more common inherited disorder of the tubular epithelium, autosomal dominant polycystic kidney disease (ADPKD), is at least in part related to mutation of polycystin 2 (PC2), a protein encoded by the PKD2 gene. PC2 is now identified as TRPP2, a Ca(2+)-permeable non-selective cation channel located on the cilia of tubular epithelial cells. TRP-related ion transport may also play a role in the pathogenesis of arterial systemic and/or pulmonary hypertension through regulation of vascular smooth muscle contraction, renal perfusion/hemodynamics, as well as the total body balance of divalent cations. Thus, multiple renal TRP channels are potential targets for pharmacological intervention aimed at preventing or attenuating the burden of chronic kidney disease.
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PMID:TRP channels as therapeutic targets in kidney disease and hypertension. 2343 67

Calcineurin inhibitors (CNIs) are immunosuppressive drugs used to prevent graft rejection after organ transplant. Common side effects include renal magnesium wasting and hypomagnesemia, which may contribute to new-onset diabetes mellitus, and hypercalciuria, which may contribute to post-transplant osteoporosis. Previous work suggested that CNIs reduce the abundance of key divalent cation transport proteins, expressed along the distal convoluted tubule, causing renal magnesium and calcium wasting. It has not been clear, however, whether these effects are specific for the distal convoluted tubule, and whether these represent off-target toxic drug effects, or result from inhibition of calcineurin. The CNI tacrolimus can inhibit calcineurin only when it binds with the immunophilin, FKBP12; we previously generated mice in which FKBP12 could be deleted along the nephron, to test whether calcineurin inhibition is involved, these mice are normal at baseline. Here, we confirmed that tacrolimus-treated control mice developed hypomagnesemia and urinary calcium wasting, with decreased protein and mRNA abundance of key magnesium and calcium transport proteins (NCX-1 and Calbindin-D28k ). However, qPCR also showed decreased mRNA expression of NCX-1 and Calbindin-D28k , and TRPM6. In contrast, KS-FKBP12-/- mice treated with tacrolimus were completely protected from these effects. These results indicate that tacrolimus affects calcium and magnesium transport along the distal convoluted tubule and strongly suggests that inhibition of the phosphatase, calcineurin, is directly involved.
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PMID:Tacrolimus-induced hypomagnesemia and hypercalciuria requires FKBP12 suggesting a role for calcineurin. 3190 54