Urine-concentrating Ability Research Articles

Angiotensin converting enzyme inhibition blocks interstitial hyaluronan dissipation in the neonatal rat kidney via hyaluronan synthase 2 and hyaluronidase 1

A functional renin–angiotensin system (RAS) is required for normal kidney development. Neonatal inhibition of the RAS in rats results in long-term pathological renal phenotype and causes hyaluronan (HA), which is involved in morphogenesis and inflammation, to accumulate. To elucidate the mechanisms, intrarenal HA content was followed during neonatal completion of nephrogenesis with or without angiotensin converting enzyme inhibition (ACEI) together with mRNA expression of hyaluronan synthases (HAS), hyaluronidases (Hyal), urinary hyaluronidase activity and cortical lymphatic vessels, which facilitate the drainage of HA from the tissue. In 6–8days old control rats cortical HA content was high and reduced by 93% on days 10–21, reaching adult low levels. Medullary HA content was high on days 6–8 and then reduced by 85% to 12-fold above cortical levels at day 21. In neonatally ACEI-treated rats the reduction in HA was abolished. Temporal expression of HAS2 corresponded with the reduction in HA content in the normal kidney. In ACEI-treated animals cortical HAS2 remained twice the expression of controls. Medullary Hyal1 increased in controls but decreased in ACEI-treated animals. Urine hyaluronidase activity decreased with time in control animals while in ACEI-treated animals it was initially 50% lower and did not change over time. Cells expressing the lymphatic endothelial mucoprotein podoplanin in ACEI-treated animals were increased 18-fold compared to controls suggesting compensation. In conclusion, the high renal HA content is rapidly reduced due to reduced HAS2 and increased Hyal1 mRNA expressions. Normal angiotensin II function is crucial for inducing these changes. Due to the extreme water-attracting and pro-inflammatory properties of HA, accumulation in the neonatally ACEI-treated kidneys may partly explain the pathological renal phenotype of the adult kidney, which include reduced urinary concentration ability and tubulointerstitial inflammation.

Autoimmunity to the Sodium-Level Sensor in the Brain Causes Essential Hypernatremia

Na(x) is the sodium-level sensor of body fluids in the brain involved in sodium homeostasis. Na(x)-knockout mice do not stop ingesting salt even when dehydrated. Here we report a case with clinical features of essential hypernatremia without demonstrable hypothalamic structural lesions, who was diagnosed as a paraneoplastic neurologic disorder. The patient had autoantibodies directed against Na(x), along with a ganglioneuroma composed of Schwann-like cells robustly expressing Na(x). The removal of the tumor did not reduce the autoantibody levels or relieve the symptoms. Intravenous injection of the immunoglobulin fraction of the patient's serum into mice induced abnormalities in water/salt intake and diuresis, which led to hypernatremia. In the brains of these mice, cell death was observed along with focal deposits of complement C3 and inflammatory infiltrates in circumventricular organs where Na(x) is specifically expressed. Our findings thus provide new insights into the pathogenesis of hypernatremia relevant to the sodium-level-sensing mechanism in humans.

Glomerular Hyperfiltration in Sickle Cell Disease

Sickle cell disease (SCD) is a monogenetic, chronic anemia syndrome that is caused by a point mutation in the β-globin gene and affects approximately 100,000 individuals in the United States. Approximately 4 to 5% of these individuals have or will develop stage 5 chronic kidney disease (CKD), and 0.11% of patients who are on long-term maintenance renal replacement therapy have SCD-associated nephropathy (1–3). Homozygous hemoglobin S leads to severe, chronic, hemolytic anemia and the propensity for hemoglobin polymerization, and red blood cell (RBC) sickling causes small artery occlusions. SCD is a multiorgan syndrome with involvement of the central nervous system (infarcts, strokes), eyes, heart, lungs (pulmonary hypertension), spleen (infarcts), muscle, bone (avascular necrosis), and kidneys. Renal complications include chronic medullary injury and papillary necrosis and transient macrohematuria, which are thought to be caused by vasa recta occlusive disease as a result of RBC sickling. Medullary injury also causes reduced urine-concentrating ability and a mild form of (type IV) distal renal tubular acidosis. Glomerular abnormalities include micro- and macroalbuminuria and the nephrotic syndrome. Histologically, FSGS is the predominant glomerular lesion in patients with SCD and proteinuria (4). Of note, …

Targeted Inactivation of EGF Receptor Inhibits Renal Collecting Duct Development and Function

The ureteric bud (UB) expresses high levels of the EGF receptor (EGFR) during kidney development, but its function in this setting is unclear. Here, Egfr mRNA was abundant in medullary portions of the UB trunk but absent from the branching UB tips during embryogenesis. Homozygous Egfr knockout did not affect the pattern of UB arborization, but renal papillae were hypoplastic and exhibited widespread apoptosis of tubular cells. Because these EGFR-deficient mice die within 1 week of life, we targeted Egfr inactivation to the renal collecting ducts using Cre-lox technology with a Hoxb7-Cre transgene. This targeted inactivation of Egfr led to a thin renal medulla, and at 7 weeks of age, the mice had moderate polyuria and reduced urine-concentrating ability. At 30 to 33 weeks, water deprivation demonstrated a continued urine-concentrating defect despite similar levels of vasopressin between knockout mice and littermate controls. Taken together, these results suggest that unlike other tyrosine kinases expressed at the UB tip, EGFR functions primarily to drive elongation of the emerging collecting ducts and to optimize urine-concentrating ability.

Phosphorylation of UT-A1 on serine 486 correlates with membrane accumulation and urea transport activity in both rat IMCDs and cultured cells

Vasopressin is the primary hormone regulating urine-concentrating ability. Vasopressin phosphorylates the UT-A1 urea transporter in rat inner medullary collecting ducts (IMCDs). To assess the effect of UT-A1 phosphorylation at S486, we developed a phospho-specific antibody to S486-UT-A1 using an 11 amino acid peptide antigen starting from amino acid 482 that bracketed S486 in roughly the center of the sequence. We also developed two stably transfected mIMCD3 cell lines: one expressing wild-type UT-A1 and one expressing a mutated form of UT-A1, S486A/S499A, that is unresponsive to protein kinase A. Forskolin stimulates urea flux in the wild-type UT-A1-mIMCD3 cells but not in the S486A/S499A-UT-A1-mIMCD3 cells. The phospho-S486-UT-A1 antibody identified UT-A1 protein in the wild-type UT-A1-mIMCD3 cells but not in the S486A/S499A-UT-A1-mIMCD3 cells. In rat IMCDs, forskolin increased the abundance of phospho-S486-UT-A1 (measured using the phospho-S486 antibody) and of total UT-A1 phosphorylation (measured by (32)P incorporation). Forskolin also increased the plasma membrane accumulation of phospho-S486-UT-A1 in rat IMCD suspensions, as measured by biotinylation. In rats treated with vasopressin in vivo, the majority of the phospho-S486-UT-A1 appears in the apical plasma membrane. In summary, we developed stably transfected mIMCD3 cell lines expressing UT-A1 and an S486-UT-A1 phospho-specific antibody. We confirmed that vasopressin increases UT-A1 accumulation in the apical plasma membrane and showed that vasopressin phosphorylates UT-A1 at S486 in rat IMCDs and that the S486-phospho-UT-A1 form is primarily detected in the apical plasma membrane.

Liver and kidney disease in ciliopathies

Hepatorenal fibrocystic diseases (HRFCDs) are among the most common inherited human disorders. The discovery that proteins defective in the autosomal dominant and recessive polycystic kidney diseases (ADPKD and ARPKD) localize to the primary cilia and the recognition of the role these organelles play in the pathogenesis of HRFCDs led to the term "ciliopathies." While ADPKD and ARPKD are the most common ciliopathies associated with both liver and kidney disease, variable degrees of renal and/or hepatic involvement occur in many other ciliopathies, including Joubert, Bardet-Biedl, Meckel-Gruber, and oral-facial-digital syndromes. The ductal plate malformation (DPM), a developmental abnormality of the portobiliary system, is the basis of the liver disease in ciliopathies that manifest congenital hepatic fibrosis (CHF), Caroli syndrome (CS), and polycystic liver disease (PLD). Hepatocellular function remains relatively preserved in ciliopathy-associated liver diseases. The major morbidity associated with CHF is portal hypertension (PH), often leading to esophageal varices and hypersplenism. In addition, CD predisposes to recurrent cholangitis. PLD is not typically associated with PH, but may result in complications due to mass effects. The kidney pathology in ciliopathies ranges from non-functional cystic dysplastic kidneys to an isolated urinary concentration defect; the disorders contributing to this pathology, in addition to ADPKD and ARPKD, include nephronophithisis (NPHP), glomerulocystic kidney disease and medullary sponge kidneys. Decreased urinary concentration ability, resulting in polyuria and polydypsia, is the first and most common renal symptom in ciliopathies. While the majority of ADPKD, ARPKD, and NPHP patients require renal transplantation, the frequency and rate of progression to renal failure varies considerably in other ciliopathies. This review focuses on the kidney and liver disease found in the different ciliopathies.

A selective EP4 PGE2 receptor agonist alleviates disease in a new mouse model of X-linked nephrogenic diabetes insipidus

X-linked nephrogenic diabetes insipidus (XNDI) is a severe kidney disease caused by inactivating mutations in the V2 vasopressin receptor (V2R) gene that result in the loss of renal urine-concentrating ability. At present,no specific pharmacological therapy has been developed for XNDI, primarily due to the lack of suitable animal models. To develop what we believe to be the first viable animal model of XNDI, we generated mice in which the V2R gene could be conditionally deleted during adulthood by administration of 4-OH-tamoxifen.Radioligand-binding studies confirmed the lack of V2R-binding sites in kidneys following 4-OH-tamoxifen treatment, and further analysis indicated that upon V2R deletion, adult mice displayed all characteristic symptoms of XNDI, including polyuria, polydipsia, and resistance to the antidiuretic actions of vasopressin. Gene expression analysis suggested that activation of renal EP4 PGE2 receptors might compensate for the lack of renal V2R activity in XNDI mice. Strikingly, both acute and chronic treatment of the mutant mice with a selective EP4 receptor agonist greatly reduced all major manifestations of XNDI, including changes in renal morphology.These physiological improvements were most likely due to a direct action on EP4 receptors expressed on collecting duct cells. These findings illustrate the usefulness of the newly generated V2R mutant mice for elucidating and testing new strategies for the potential treatment of humans with XNDI.

Variation in urine concentrating ability and water balance of the Black-tailed Tree Rat Thallomys nigricauda, along an aridity gradient

Mechanisms behind variation in physiological traits may assist in explaining how certain traits have evolved. The ability of mammals to concentrate urine has been seen as an adaptation to xeric environments. Urine osmolality and relative medullary thickness (RMT) are two indices which indicate urine concentrating powers. In addition, mammals living in xeric regions have lower water turnover rates (WTR) than their mesic counterparts. The RMT, urine concentrating ability (UCA) and WTR of the Black-tailed Tree Rat, Thallomys nigricauda, were investigated at three study sites along an aridity gradient. We investigated the extent to which these traits are influenced by evolutionary adaptation and/or phenotypic flexibility. There was no significant difference in RMT between sites and no difference in osmolalities when site and season were taken into account. In addition, there was no significant effect of site and season on WTR. This suggests that these traits might have a genetic basis, and reflect an evolutionary adaptation. Lack of differences in the renal traits in T. nigricauda across their range may be interpreted as lack of phenotypic flexibility. However, as a consequence of the degree of individual variation in the parameters measured there appears to be phenotypic flexibility with individuals responding to their specific conditions. This has positive implications for the survival of the species in the light of climate change.

Novel missense mutation of uromodulin in mice causes renal dysfunction with alterations in urea handling, energy, and bone metabolism

Uromodulin-associated kidney disease is a heritable renal disease in humans caused by mutations in the uromodulin (UMOD) gene. The pathogenesis of the disease is mostly unknown. In this study, we describe a novel chemically induced mutant mouse line termed Umod(A227T) exhibiting impaired renal function. The A227T amino acid exchange may impair uromodulin trafficking, leading to dysfunction of thick ascending limb cells of Henle's loop of the kidney. As a consequence, homozygous mutant mice display azotemia, impaired urine concentration ability, reduced fractional excretion of uric acid, and a selective defect in concentrating urea. Osteopenia in mutant mice is presumably a result of chronic hypercalciuria. In addition, body composition, lipid, and energy metabolism are indirectly affected in heterozygous and homozygous mutant Umod(A227T) mice, manifesting in reduced body weight, fat mass, and metabolic rate as well as reduced blood cholesterol, triglycerides, and nonesterified fatty acids. In conclusion, Umod(A227T) might act as a gain-of-toxic-function mutation. Therefore, the Umod(A227T) mouse line provides novel insights into consequences of disturbed uromodulin excretion regarding renal dysfunction as well as bone, energy, and lipid metabolism.

Studies in urinary tract infections. IV. Urinary leucocyte excretion in bacteriuria.

Abstract Methods for the determination of leucocyte excretion in the urine have been studied, and an investigation has been made of the relationship between pyuria and bacteriuria. All of 42 women with no evidence of urinary tract disease excreted fewer than 400,000 leucocytes per hour, while 144 out of 152 women with bacteriuria excreted more than 400,000 leucocytes per hour, regardless of the type of bacteria isolated from the urine. Among these patients the excretion rate was found to be higher in those with impaired urine concentration ability, i.e. with signs of pyelonephritis. Pyuria can be diagnosed by estimation of the leucocyte excretion rate or by determination of the leucocyte concentration in the urine. There were more than 10 leucocytes per mm3 of urine in 97% of the specimens from 164 patients who excreted more than 400,000 leucocytes per hour. Ten or fewer leucocytes per mm3 were found in the urine from 92% of the 71 subjects who had excretion rates below 400,000 leucocytes per hour. With the technique employed for microscopic examination of the urinary sediment, the finding of three or more leucocytes per high-power field indicates pyuria; if there are fewer than three, pyuria cannot, however, be ruled out.

SOD1‐deficiency causes salt‐sensitivity and aggravates hypertension in hydronephrosis

We investigated the role of oxidative stress for salt‐sensitivity and for hypertension in hydronephrosis (HN).HN was induced in SOD1‐transgenic (SOD1‐tg), SOD1‐deficient (SOD1‐ko) and wild‐type mice. Telemetric blood pressure measurements were performed during normal and high sodium conditions. Excretion of F2‐IsoP and histology were investigated and the effects of Tempol on blood pressure and TGF were studied.HN wild‐type mice developed salt‐sensitive hypertension (114±1 to 120±2 mmHg) which was augmented in SOD1‐ko mice (125±3 to 135±4 mmHg), but abolished in SOD1‐tr mice (109±3 to 108±3 mmHg). SOD1‐ko controls displayed salt‐sensitive blood pressure (108±1 to 115±2 mmHg), which was not found in wild‐type or SOD1‐tg mice. HN wild‐type and SOD1‐ko mice exhibited increased urine flows, increased urinary excretion of F2‐IsoP, and impaired urine concentration ability. An increased excretion of F2‐IsoP was also found in SOD1‐ko controls. The renal histopathological changes found in HN wild‐types were augmented in SOD1‐ko and diminished in SOD‐tg mice. Tempol attenuated blood pressure and normalized the abnormal TGF in HN.Oxidative stress due to SOD1‐deficiency is associated with salt‐sensitivity and plays an important role for the development of hypertension in HN. Increased superoxide formation can enhance the TGF response and thereby be involved in the development of hypertension.

Acute and chronic metabolic acidosis interferes with aquaporin-2 translocation in the rat kidney collecting ducts

Renal aquaporin-2 (AQP2) expression plays a key role in urine concentration. However, it is not known whether metabolic acidosis affects urine-concentrating ability through AQP2 expression in the kidney and urine. We examined urinary excretion and renal expression of AQP2 in control and acidosis rats, using RT-competitive PCR, immunoblot and immunocytochemistry. Urinary excretion of AQP2 is decreased by 92% even with the increase in AQP2 mRNA and protein expressions in the collecting ducts by metabolic acidosis in rats. Urine osmolality in control rats was 1670+/-198 mOsm per kg H(2)O, and immunocytochemistry revealed the presence of AQP2 in the apical plasma membrane of the principal cells in the collecting ducts. Urine osmolality in acidosis rats was lower than that in control (1397+/-243 mOsm per kg H(2)O), and immunocytochemistry showed the diffuse presence of AQP2 in the cytoplasm of the principal cells. Differential centrifugation-coupled immunoblot showed a significant decrease in the ratio of AQP2 in plasma membrane-enriched fraction to that in intracellular vesicle-enriched fraction by metabolic acidosis. In summary, AQP2 translocation is largely decreased by metabolic acidosis even with increased expression in the collecting ducts. A disorder of AQP2 translocation in the collecting ducts with acidosis may be responsible for the diuresis in patients with chronic renal failure.

A different hypothesis on hyponatremia in psychiatric patients: Treatment implications and experiences

Polydipsia, chronic or intermittent, with or without hyponatremia, frequently occurs among chronic patients with schizophrenia. The pathogenesis of polydipsia remains poorly understood. The key assumption of our hypothesis is that in some of these patients, polydipsia and hyponatremia are consequences of patients’ adjustment to a prolonged intake of an insufficient diet, dominantly poor in potassium. Deficits of potassium, without significant hypokalemia, may cause impairment of the urine-concentrating ability with polyuria-polydipsia. A fall of intracellular tonicity, dominantly due to a decreased amount of K+ and attendant anions in cells, should be accompanied with a fall of extracellular osmolality. Because of the diminished content of ions that may diffuse out of cells and because osmotic equilibrium between the ECF and ICF compartments cannot be established in a short period of time, these patients have a diminished ability to adapt to an excessive intake of fluids. These mechanisms might be related to the development of polydipsia and water intoxication in patients with different mental and somatic disorders. The experiences with the therapeutic effects of diets containing an sufficient amount of potassium in two patients with schizophrenia are described. Further investigations are needed, and we suggest a possible approach to test our hypotheses.

Jouberin localizes to collecting ducts and interacts with nephrocystin-1

Joubert syndrome and related disorders are autosomal recessive multisystem diseases characterized by cerebellar vermis aplasia/hypoplasia, retinal degeneration and cystic kidney disease. There are five known genes; mutations of which give rise to a spectrum of renal cystic diseases the most common of which is nephronophthisis, a disorder characterized by early loss of urinary concentrating ability, renal fibrosis, corticomedullary cyst formation and renal failure. Many of the proteins encoded by these genes interact with one another and are located at adherens junctions or the primary cilia and or basal bodies. Here we characterize Jouberin, a multi-domain protein encoded by the AHI1 gene. Immunohistochemistry with a novel antibody showed that endogenous Jouberin is expressed in brain, kidney and HEK293 cells. In the kidney, Jouberin co-localized with aquaporin-2 in the collecting ducts. We show that Jouberin interacts with nephrocystin-1 as determined by yeast-2-hybrid system and this was confirmed by exogenous and endogenous co-immunoprecipitation in HEK293 cells. Jouberin is expressed at cell-cell junctions, primary cilia and basal body of mIMCD3 cells while a Jouberin-GFP construct localized to centrosomes in subconfluent and dividing MDCK cells. Our results suggest that Jouberin is a protein whose expression pattern supports both the adherens junction and the ciliary hypotheses for abnormalities leading to nephronophthisis.

Immature Renal Structures Associated With a Novel UMOD Sequence Variant

Mutations of the UMOD gene, encoding uromodulin, have been associated with medullary cystic kidney disease 2, familial juvenile hyperuricemic nephropathy, and glomerulocystic kidney disease. We report on a 13-year-old boy presenting with chronic reduced kidney function, hyperuricemia, and impairment in urine-concentrating ability. His father was affected by an undefined nephropathy that required transplantation. The boy's renal ultrasonography showed reduced bilateral kidney volumes and cortical hyperechogenicity, with 2 tiny cysts in the left kidney. Renal biopsy showed up to 60% of glomeruli featuring an enlargement of Bowman space (glomerular cysts), with mild interstitial fibrosis (alpha-smooth muscle actin [alphaSMA] positive), inflammatory infiltrate, and focal tubular atrophy at the cortical level. At the corticomedullary junction, immature tubules (some dilated) with cytokeratin- and paired box gene 2 (PAX2)-positive immunostaining were seen, surrounded by vimentin-positive mesenchymal tissue. Unlike previously reported cases, no uromodulin-positive globular aggregates within the cytoplasm of tubular cells were observed. Uromodulin urinary excretion was absent. Genetic analysis showed a novel heterozygous sequence change in the UMOD gene (NM_003361.2:c.149G-->C; p.Cys50Ser) involving the first epidermal growth factor-like domain of the protein in both the boy and his father. This novel UMOD sequence variant, which is associated with an immunohistochemical pattern different from previous reports and a histological picture characterized by immature renal structures, suggests a possible role for UMOD in renal development.

Nephrocystin-1 interacts directly with Ack1 and is expressed in human collecting duct

Nephronophthisis is characterised by renal fibrosis, tubular basement membrane disruption and corticomedullary cyst formation leading to end stage renal failure. Mutations in NPHP1 account for the underlying genetic defect in 25% of patients with nephronophthisis. Loss of urine concentration ability may be an early feature of nephronophthisis. Using yeast-2-library screening with the SH3 domain of nephrocystin-1 as bait, we identify Ack1 as a novel interaction partner. This interaction is confirmed using exogenous over-expression followed by co-immunoprecipitation. Ack1 is an activated Cdc42-associated kinase, and like nephrocystin-1, is a known interactor of p130Cas. Nephrocystin-1 partially colocalises with Ack1 at cell–cell contacts in IMCD3 cells. In human kidney, nephrocystin-1 expression is limited to cell–cell junctions in renal collecting duct cells. These data define Ack1 as a novel interaction partner of nephrocystin-1 and implicate cell–cell junctions and the renal collecting duct in the pathology of nephronophthisis.

Pentoxifylline prevents the meglumine antimonate-induced renal toxicity in rats, but not that induced by the inorganic antimony pentachloride

Tumor necrosis factor-alpha (TNF-α) is a mediator of inflammation and has an important role in human and experimental renal diseases. Pentoxifylline (PTX) has been shown to inhibit cytokine synthesis, including TNF-α. The aim of the present study was to examine the effect of PTX on meglumine antimonate (Sb V) and antimony pentachloride (SbCl 5)-induced renal toxicity in rats. Sixty Wistar rats were divided into six groups according to the treatment employed over the period of 7 days: group I—saline (NaCl 0.9%); group II—PTX plus saline; group III—meglumine antimonate (Sb V) plus saline; group IV—meglumine antimonate (Sb V) plus PTX; group V—SbCl 5 plus saline; group VI—SbCl 5 with PTX. The animals’ urinary concentration ability was evaluated before and after the end of the treatment. Urine and blood osmolality, sodium and creatinine concentration, and urine volume per minute ( V) were determined. Creatinine clearance (CrCl), fractional sodium excretion (FE Na), and urine to plasma osmolality ratio (U/P osm) were calculated. TNF-α concentration in blood was assessed. On the seventh day, the animals were sacrificed and their kidneys were submitted to histological analysis. The meglumine antimonate (Sb V)-treated animals showed an impaired renal capacity to concentrate urine, with low values of the ratio U/P osm, reduction in CrCl, and an increment in TNF-α serum levels. PTX associated with meglumine antimonate (Sb V) reduced TNF-α serum levels and was effective in preventing renal functional alterations. Rats treated with SbCl 5 showed functional and histopathologic alterations compatible with acute tubular necrosis, and treatment with PTX did not prevent SbCl 5-induced nephrotoxicity. PTX was effective in preventing renal functional alterations induced by meglumine antimonate (Sb V) in rats.

Analgesic nephropathy

Analgesic nephropathy

Postnatal adrenalectomy impairs urinary concentrating ability by increased COX-2 and leads to renal medullary injury

We hypothesized that aldosterone promotes development of the renal medulla in the postnatal period and that cyclooxygenase-2 (COX-2) activity contributes to renal dysfunction after impaired aldosterone signaling. To test these hypotheses, rat pups underwent either sham operation or adrenalectomy at postnatal day 10. Adrenalectomized rats were divided into no steroid substitution (ADX), corticosterone replacement (ADX-C), and corticosterone and DOCA substitution (ADX-CD) groups that received subcutaneous pellets with steroids. Without replacement, pups failed to thrive and exhibited impaired urinary-concentrating ability. The renal medulla was significantly smaller, and the medullary interstitial osmolality was lower in the ADX group, whereas COX-2 and PGE2 tissue levels were significantly elevated compared with levels shown in sham animals. Substitution with DOCA and corticosterone corrected these changes, whereas corticosterone replacement alone improved survival but not weight gain and urinary-concentrating ability. Administration of a COX-2 inhibitor to ADX rats (parecoxib, 5 mg.kg(-1).day(-1), days 17-20) increased weight gain, urinary-concentrating ability, and papillary osmolality. After fluid deprivation, parecoxib attenuated weight loss and the increase in plasma Na+ concentration and osmolality. It is concluded that mineralocorticoid is required for normal postnatal development of the renal medulla. COX-2 contributes to impaired urine-concentrating ability, NaCl loss, and extracellular volume depletion in postnatal mineralocorticoid deficiency.

Genotype and phenotype correlation of calcium-sensing receptor variants

Mutations of the calcium-sensing receptor (CaR) gene give rise to disorders of renal calcium excretion. It is now demonstrated that even common variants of CaR can cause alteration in tissue sensitivity to extracellular calcium and are associated with primary hypercalciuria. Agents targeting these functional domains may well be an option for the management of hypercalciuria and renal stones.