Biomedical subjects

Volker Vallon

Publications and source records attributed to Volker Vallon.

At least 37 records · Page 2Linked to original sources

PubMed2005

Enhanced passive Ca2+ reabsorption and reduced Mg2+ channel abundance explains thiazide-induced hypocalciuria and hypomagnesemia.

Thiazide diuretics enhance renal Na+ excretion by blocking the Na+-Cl- cotransporter (NCC), and mutations in NCC result in Gitelman syndrome. The mechanisms underlying the accompanying hypocalciuria and hypomagnesemia remain debated. Here, we show that enhanced passive Ca2+ transport in the proximal tubule rather than active Ca2+ transport in distal convolution explains thiazide-induced hypocalciuria. First, micropuncture experiments in mice demonstrated increased reabsorption of Na+ and Ca2+ in the proximal tubule during chronic hydrochlorothiazide (HCTZ) treatment, whereas Ca2+ reabsorption in distal convolution appeared unaffected. Second, HCTZ administration still induced hypocalciuria in transient receptor potential channel subfamily V, member 5-knockout (Trpv5-knockout) mice, in which active distal Ca2+ reabsorption is abolished due to inactivation of the epithelial Ca2+ channel Trpv5. Third, HCTZ upregulated the Na+/H+ exchanger, responsible for the majority of Na+ and, consequently, Ca2+ reabsorption in the proximal tubule, while the expression of proteins involved in active Ca2+ transport was unaltered. Fourth, experiments addressing the time-dependent effect of a single dose of HCTZ showed that the development of hypocalciuria parallels a compensatory increase in Na+ reabsorption secondary to an initial natriuresis. Hypomagnesemia developed during chronic HCTZ administration and in NCC-knockout mice, an animal model of Gitelman syndrome, accompanied by downregulation of the epithelial Mg2+ channel transient receptor potential channel subfamily M, member 6 (Trpm6). Thus, Trpm6 downregulation may represent a general mechanism involved in the pathogenesis of hypomagnesemia accompanying NCC inhibition or inactivation.

Animals↗

PubMed2005

The salt paradox and its possible implications in managing hypertensive diabetic patients.

Diabetes mellitus is one of the leading causes of end-stage renal disease. The pathogenesis of diabetic nephropathy is still poorly understood, but glomerular injury has been ascribed, at least in part, to glomerular hyperfiltration, which occurs early in the course of diabetes mellitus. Therefore, a better understanding of the early dysfunctions observed in the diabetic kidney may permit the development of new strategies to prevent diabetic nephropathy. In this review, we discuss the pathophysiology for the paradoxical relationship between dietary salt and glomerular filtration rate observed in early diabetes mellitus and possible implications in managing diabetic patients.

Animals↗

PubMed2005

New insights into the role of serum- and glucocorticoid-inducible kinase SGK1 in the regulation of renal function and blood pressure.

PURPOSE OF REVIEW: The serum and glucocorticoid inducible kinase 1 (SGK1) is induced in the aldosterone sensitive distal nephron (ASDN) where it may stimulate Na reabsorption, partly by inhibiting ubiquitin ligase Nedd4-2-mediated retrieval of epithelial Na+ channel ENaC from the luminal membrane. We describe recent advances in our understanding of SGK1 function in the regulation of renal function and blood pressure. RECENT FINDINGS: Thiazolidinediones, i.e. activators of peroxisome proliferator-activated receptor gamma (PPAR gamma), upregulate SGK1 and ENaC mRNA expression and increase cell-surface expression of ENaC alpha in a human cortical-collecting-duct cell line. cAMP/protein kinase A can induce phosphorylation and inhibition of Nedd4-2-independent of SGK1. Part of ENaC stimulation by SGK1 appears dependent on a SGK1 consensus motif in ENaC alpha and independent of Nedd4-2. SGK1-dependent upregulation of Na+ reabsorption in ASDN contributes to upregulation of renal K+ excretion. In oocytes, SGK1 activates various renal transport proteins including Na+/glucose cotransporter SGLT1, Na+-coupled dicarboxylate transporter NaDC-1, epithelial Ca+ channel TRPV5, renal outer medullary K+ channel ROMK and voltage gated K+ channels KCNE1/KCNQ1 and Kv1.3. A variant of the SGK1 gene associates with increased blood pressure and body mass index. SUMMARY: PPAR gamma activators may increase renal Na reabsorption by stimulating SGK1 and ENaC. Nedd4-2 integrates influences of cAMP/protein kinase A and SGK1. SGK1 can activate ENaC in part directly and independent of Nedd4-2. K+ homeostasis requires SGK1-dependent Na+ reabsorption in ASDN. SGK1 may affect renal transport mechanisms beyond Na+ reabsorption and K+ secretion in ASDN. Polymorphisms of SGK1 may be relevant to the pathophysiology of hypertension and other diseases.

Blood Pressure↗

PubMed2005

Role of Sgk1 in salt and potassium homeostasis.

Aldosterone plays a pivotal role in NaCl and K(+) homeostasis by stimulation of Na(+) reabsorption and K(+) secretion in the aldosterone-sensitive distal nephron (ASDN). Recent studies demonstrated that the serum- and glucocorticoid-regulated kinase 1 (Sgk1) is induced by aldosterone in the ASDN and that polymorphisms of the kinase associate with arterial blood pressure in normotensive subjects. This review discusses the role of Sgk1 in NaCl and K(+) homeostasis as evidenced by in vivo studies, including those in Sgk1-deficient mice. The studies indicate that Sgk1 is not absolutely required for Na(+) reabsorption and K(+) secretion in the ASDN. On a standard NaCl and K(+) diet, modestly enhanced plasma aldosterone concentrations appear sufficient to establish a compensated phenotype in the absence of Sgk1. The kinase is necessary, however, for upregulation of transcellular Na(+) reabsorption in the ASDN. This may involve Sgk1-mediated stimulation of basolateral Na(+)-K(+)-ATPase as well as retention of epithelial Na(+) channel, ENaC, in the apical membrane. Such an upregulation is a prerequisite for adequate adaptation of 1) renal NaCl reabsorption during restricted dietary NaCl intake, as well as 2) K(+) secretion in response to enhanced K(+) intake. Thus gain-of-function mutations of Sgk1 are expected to result in renal NaCl retention and enhanced K(+) secretion. Further studies are required to elucidate renal and nonrenal aldosterone-induced effects of Sgk1, the role of other Sgk1 activators, as well as the link of Sgk1 polymorphisms to arterial hypertension in humans.

Aldosterone↗

PubMed2005

SGK1 as a determinant of kidney function and salt intake in response to mineralocorticoid excess.

Mineralocorticoids modify salt balance by both stimulating salt intake and inhibiting salt loss. Renal salt retention is accomplished by upregulation of reabsorption, an effect partially mediated by serum- and glucocorticoid-inducible kinase 1 (SGK1). The present study explored the contribution of SGK1 to the regulation of renal function, salt intake, and blood pressure during mineralocorticoid excess. DOCA/1% NaCl treatment increased blood pressure and creatinine clearance to a similar extent in SGK1-deficient sgk1(-/-) and wild-type sgk1(+/+) mice but led to more pronounced increase of proteinuria in sgk1(+/+) mice (by 474 +/- 89%) than in sgk1(-/-) mice (by 154 +/- 31%). DOCA/1% NaCl treatment led to significant increase of kidney weight (by 24%) and to hypokalemia (from 3.9 +/- 0.1 to 2.7 +/- 0.1 mmol/l) only in sgk1(+/+) mice. The treatment enhanced renal Na(+) excretion significantly more in sgk1(+/+) mice (from 3 +/- 1 to 134 +/- 32 micromol.24 h(-1).g body wt(-1)) than in sgk1(-/-) mice (from 4 +/- 1 to 49 +/- 8 micromol.24 h(-1).g body wt(-1)), pointing to SGK1-dependent stimulation of salt intake. With access to two drinking bottles containing 1% NaCl or water, DOCA treatment did not significantly affect water intake in either genotype but increased 1% NaCl intake in sgk1(+/+) mice (within 9 days from 3.5 +/- 0.9 to 16.5 +/- 2.4 ml/day) consistent with DOCA-induced salt appetite. This response was significantly attenuated in sgk1(-/-) mice (from 2.6 +/- 0.6 to 5.9 +/- 0.9 ml/day). Thus SGK1 contributes to the stimulation of salt intake, kidney growth, proteinuria, and renal K(+) excretion during mineralocorticoid excess.

Animals↗

PubMed2004

Requirement of intact adenosine A1 receptors for the diuretic and natriuretic action of the methylxanthines theophylline and caffeine.

Although the diuretic and natriuretic effects of the methylxanthines caffeine and theophylline are well established, the mechanisms responsible for these effects are unclear and may be related to inhibition of phosphodiesterases and/or antagonism of adenosine receptors. With regard to the latter, pharmacological blockade of A1 receptors can induce diuresis and natriuresis by inhibition of proximal tubular reabsorption. To elucidate the role of the A1 receptor in renal actions of methylxanthines, experiments were performed in A1 receptor knockout (A1R-/-) and littermate wild-type (A1R+/+) mice. Urinary excretion was determined in awake mice in metabolic cages over 3 h in response to theophylline (as theophylline2/ethylenediamine, 45 mg/kg), caffeine (45 mg/kg), or vehicle (0.9 ml/30 g b.wt. of 0.85% NaCl) given by oral gavage. Theophylline and caffeine elicited a diuresis and natriuresis (in absolute terms and related to urinary creatinine excretion) in A1R+/+ but not in A1R-/- mice. In a second series, the renal effect of intravenous application of theophylline (30 mg/kg) was determined in clearance experiments under anesthesia. This study revealed that the blunted diuretic and natriuretic effect of theophylline in A1R-/- mice was not due to different responses in blood pressure or glomerular filtration rate. The data indicate that an intact A1 receptor is necessary for caffeine- and theophylline-induced inhibition of renal reabsorption causing diuresis and natriuresis. This is consistent with the assumption that A1 receptor blockade mediates these effects.

Anesthesia↗

PubMed2004

Immunolocalization of protein kinase C isoenzymes alpha, beta I, beta II, delta, and epsilon in mouse kidney.

Localization of protein kinase C (PKC) isoenzymes alpha, beta I, beta II, delta, and epsilon was studied employing Western blot analysis and immunohistochemical methods including confocal laser-scanning microscopy in the kidney of two mice strains, namely, C57BL/6 and 129/Sv, which have recently been used as genetic backgrounds for respective knockout mice. Immunoblot analysis identified immunoreactive bands for each isoenzyme in total kidney cell extracts. Isoenzyme expression sites were identical for both strains. Glomeruli expressed PKC-alpha, -beta I, and -epsilon. The latter isoenzyme was also detected in apical aspects of proximal convoluted but not in proximal straight tubules. In contrast to rats, neither PKC-alpha nor PKC-beta I was detectable in the proximal tubule. Immunofluorescence was observed in luminal membranes of medullary (MTAL) and cortical thick ascending limbs for PKC-beta I and in MTAL for PKC-epsilon. The cortical collecting duct expressed PKC-alpha, -beta I, and -delta in intercalated cells only. In the outer medullary collecting duct, PKC-alpha and -beta I were detectable in principal cells, whereas PKC-delta was found in intercalated cells. In the inner medullary collecting duct, PKC-alpha, -beta I, and -beta II were detected. As described for the rat, the expression of PKC-beta II was otherwise restricted to cortical and medullary interstitial cells. The specificity of all labeling was confirmed in respective PKC isoenzyme knockout mice. In summary, distinct expression patterns were shown for PKC isoenzymes alpha, beta I, beta II, delta, and epsilon in the mouse kidney.

Animals↗

PubMed2004

Evidence for a role of protein kinase C-alpha in urine concentration.

In mouse kidney, the conventional protein kinase C (PKC) isoenzyme alpha is expressed in glomeruli, the cortical collecting duct (intercalated cells only), and medullary collecting duct. To get insights on its function, PKC-alpha knockout (-/-) and wild-type (+/+) mice were studied. When provided free access to water, PKC-alpha -/- mice showed approximately 50% greater urine flow rate and lower urinary osmolality in 24-h metabolic cage experiments despite a greater urinary vasopressin-to-creatinine ratio vs. PKC-alpha +/+ mice. Renal albumin excretion was not different. Clearance experiments under inactin/ketamine anesthesia revealed a modestly reduced glomerular filtration rate and showed a reduced absolute and fractional renal fluid reabsorption in PKC-alpha -/- mice. The sodium-restricting response to a low-sodium diet was unaffected in PKC-alpha -/- mice. Urinary osmolality was reduced to similar hypotonic levels in PKC-alpha -/- and +/+ mice during acute oral water loading or application of the vasopressin V(2)-receptor antagonist SR-121463. In comparison, the lower urinary osmolality observed in PKC-alpha -/- mice vs. wild-type mice under basal conditions persisted during water restriction for 36 h. In conclusion, PKC-alpha appears not to play a major role in renal sodium reabsorption but, consistent with its expression in the medullary collecting duct, contributes to urinary concentration in mice. Considering that PKC-beta I and -beta II are coexpressed with PKC-alpha in mouse medullary collecting duct, the present results indicate that conventional PKC isoenzymes cannot fully compensate for each other.

Animals↗

PubMed2004

Impaired regulation of renal K+ elimination in the sgk1-knockout mouse.

Serum- and glucocorticoid-regulated kinase 1 (Sgk1) contributes to Na+ reabsorption in the aldosterone-sensitive distal nephron. Sgk1-knockout (sgk1-/-) and littermate wild-type mice (sgk1+/+) were used to test the importance of Sgk1 in renal elimination of K+ . Intravenous application of K+ load under anesthesia increased plasma K+ concentration by 1.3 to 1.4 mM in both sgk1-/- (n = 6) and sgkl+/+ (n = 7) mice. However, the increase of absolute and fractional renal K+ excretion observed in sgk1+/+ was significantly blunted in sgk1-/- animals. Both groups of mice decreased or increased renal K+ excretion to a similar extent after a low (<0.03%) or high (5%) K+ diet for 6 d, respectively. In sgk1+/+, plasma K+ concentration was not significantly modified by either high or low K+ diet. In sgk1-/-, however, high K+ diet enhanced plasma K+ concentration by about 1.6 mM, despite an excessive increase of plasma aldosterone concentration reaching values about sixfold higher than in sgk1+/+. Electrophysiological and immunohistochemical studies under high K+ diet indicated that reduced epithelial Na+ channel ENaC and/or Na+/K+-ATPase activity in the aldosterone-sensitive distal nephron accounted for the impaired response in sgk1-/- and that an enhanced apical abundance of renal outer medullary K+ channel ROMK partly compensated for the defect. The acute and chronic regulation of renal K+ elimination involves Sgk1.

Animals↗

PubMed2004

Altered renal distal tubule structure and renal Na(+) and Ca(2+) handling in a mouse model for Gitelman's syndrome.

Gitelman's syndrome, an autosomal recessive renal tubulopathy caused by loss-of-function mutations in the thiazide-sensitive NaCl co-transporter (NCC) of the distal convoluted tubule (DCT), is characterized by mild renal Na(+) wasting, hypocalciuria, hypomagnesemia, and hypokalemic alkalosis. For gaining further insights into the pathophysiology of Gitelman's syndrome, the impact of NCC ablation on the morphology of the distal tubule, on the distribution and abundance of ion transport proteins along its length, and on renal tubular Na(+) and Ca(2+) handling in a gene-targeted mouse model was studied. NCC-deficient mice had significantly elevated plasma aldosterone levels and exhibited hypocalciuria, hypomagnesemia, and compensated alkalosis. Immunofluorescent detection of distal tubule marker proteins and ultrastructural analysis revealed that the early DCT, which physiologically lacks epithelial Na(+) (ENaC) and Ca(2+) (TRPV5) channels, was virtually absent in NCC-deficient mice. In contrast, the late DCT seemed intact and retained expression of the apical ENaC and TRPV5 as well as basolateral Na(+)-Ca(2+) exchanger. The connecting tubule exhibited a marked epithelial hypertrophy accompanied by an increased apical abundance of ENaC. Ca(2+) reabsorption seemed unaltered in the distal convolution (i.e., the DCT and connecting tubule) as indicated by real-time reverse transcription-PCR, Western blotting, and immunohistochemistry for TRPV5 and Na(+)-Ca(2+) exchanger and micropuncture experiments. The last experiments further indicated that reduced glomerular filtration and enhanced fractional reabsorption of Na(+) and Ca(2+) upstream and of Na(+) downstream of the DCT provide some compensation for the Na(+) transport defect in the DCT and contribute to the hypocalciuria. Thus, loss of NCC leads to major structural remodeling of the renal distal tubule that goes along with marked changes in glomerular and tubular function, which may explain some of the clinical features of Gitelman's syndrome.

Alkalosis↗

PubMed2004

Kidney function in early diabetes: the tubular hypothesis of glomerular filtration.

At the onset of diabetes mellitus, the glomerular filtration rate becomes supranormal. Discovery science has identified many abnormalities in the early diabetic kidney that apparently contribute to this phenotype. A serviceable understanding of the early diabetic kidney requires this information to fit together. It is the purpose of this article to present an archetype that explains multiple nuances of kidney function in early diabetes. We refer to this archetype as the "tubular hypothesis of glomerular filtration." Its basic tenet is that strange effects of diabetes on glomerular filtration stem from primary effects on the proximal tubule or loop of Henle that impact glomerular filtration by feedback through the macula densa. This theory can explain diabetic hyperfiltration, a paradoxical effect of dietary salt on glomerular filtration rate in diabetes, and the renal response to dietary protein and amino acid infusion in diabetes. The discussion centers on the kidney as an integrated system of parts rather than on the specific cellular mechanisms that comprise those parts.

Animals↗

PubMed2003

Emotional instability but intact spatial cognition in adenosine receptor 1 knock out mice.

Several lines of evidence point to the involvement of adenosine in the regulation of important central mechanisms such as cognition, arousal, aggression and anxiety. In order to elucidate the involvement of the adenosine A1 receptor (A1AR) in spatial learning and the control of exploratory behaviour, we assessed A1AR knockout mice (A1AR-/-) and their wild-type littermates (A1AR+/+) in a place navigation task in the water maze and in a battery of forced and free exploration tests. In the water maze, A1AR-/- mice showed normal escape latencies and were indistinguishable from controls with respect to measures of spatial performance during both training and probe trial. But despite normal performance they showed increased wall hugging, most prominently after the relocation of the goal platform for reversal training. Quantitative analysis of strategy choices indicated that wall hugging was increased mainly at the expense of chaining and passive floating, whereas the frequency of trials characterised as direct swims or focal searching was normal in A1AR-/- mice. These results indicate intact spatial cognition, but mildly altered emotional reactions to the water maze environment. In line with this interpretation, A1AR-/- mice showed normal levels and patterns of activity, but a mild increase of some measures of anxiety in our battery of forced and free exploration paradigms. These results are in line with findings published using a genetically similar line, but demonstrate that the magnitude of the changes and the range of affected behavioural measures may vary considerably depending on the environmental conditions during testing.

Animals↗

PubMed2003

Glomerular hyperfiltration and the salt paradox in early [corrected] type 1 diabetes mellitus: a tubulo-centric view.

Diabetes mellitus contributes greatly to morbidity, mortality, and overall health care costs. In major part, these outcomes derive from the high incidence of progressive kidney dysfunction in patients with diabetes making diabetic nephropathy a leading cause of end-stage renal disease. A better understanding of the early dysfunctions observed in the diabetic kidney may permit the development of new strategies to prevent diabetic nephropathy. This review proposes a "tubulo-centric" view of glomerular function in early type I diabetes mellitus. The following are particularly discussed (1) the primary role of an increase in reabsorption by the proximal tubule in early glomerular hyperfiltration, (2) the role of sodium-glucose cotransport and tubular growth under these conditions, and (3) the primary role of reabsorption by the proximal tubule for the paradoxical relationship between dietary salt and glomerular filtration rate. Finally, an outline is presented of potential therapeutic implications for the prevention of diabetic kidney disease.

Absorption↗

PubMed2003

Tubuloglomerular feedback and the control of glomerular filtration rate.

In every nephron the glomerular filtration rate is adapted to changes in the salt concentration of early distal tubular fluid through the mechanism of tubuloglomerular feedback. Recent studies indicate that adenosine and possibly ATP mediate this mechanism and demonstrate its role in glomerular hemodynamic alterations in the early diabetic kidney.

Animals↗

PubMed2003

Regulation of channels by the serum and glucocorticoid-inducible kinase - implications for transport, excitability and cell proliferation.

The serum and glucocorticoid-inducible kinase SGK1 stimulates the Na+ channels ENaC and SCN5A, the K+ channels ROMK1, Kv1.3, and KCNE1/KCNQ1, the cation conductance induced by 4F2/LAT1 and the chloride conductance induced by CFTR. The isoforms SGK2 and SGK3 have similarly been shown to regulate ENaC, SCN5A, Kv1.3 and KCNE1/KCNQ1. The kinases regulate channel abundance in the plasma membrane in part by inhibition of the ubiquitin ligase Nedd4-2 and in part by interaction with trafficking molecules such as the Na+/H+ exchanger regulating factor NHERF2. An in vivo role of SGK1 mediated ENaC channel regulation in renal salt excretion and blood pressure control is documented by the impaired ability of SGK1 knockout mice to adequately reduce renal Na+ output and maintain blood pressure during dietary salt restriction and by enhanced blood pressure in individuals carrying certain polymorphisms in the SGK1 gene. The in vivo physiological significance of SGK dependent regulation of the other channels remains to be shown even though circumstantial evidence points to involvement in the regulation of epithelial transport, cell volume, cell proliferation, cardiac action potential and neuroexcitability. There is little doubt that further channels will be identified which are modulated by the SGKs and that further in vivo physiological functions will be defined where channel regulation by the SGKs plays a critical role.

Animals↗

PubMed2003

In vivo studies of the genetically modified mouse kidney.

Gene-targeted mice provide a powerful approach to study the physiological and pathophysiological role of a given protein in kidney function and can give insights on the functional importance of these proteins under in vivo conditions as well as on the potential compensating mechanisms in their absence. Full utilisation of these animal models requires adaptation of the respective methods to the size of the mouse. This applies especially to in vivo studies in mice which have to deal with rather small structures and volumes, e.g. vessels for cannulation, plasma volumes or urinary flow rates. Here some aspects which can help to study kidney function in the mouse in vivo are outlined. The applicability of these in vivo methods are stressed by reviewing their very recent application in mice being deficient for either ROMK or SGK1.

Animals↗

PubMed2003

Blunted apoptosis of erythrocytes from taurine transporter deficient mice.

In nucleated cells cellular taurine is released prior to DNA fragmentation and the breakdown of phosphatidylserine asymmetry within the plasma membrane. Similar to what is seen in nucleated cells, phosphatidylserine asymmetry is also abolished in erythrocytes exposed to osmotic shock or oxidative stress. The present study has been performed to explore the sensitivity of erythrocytes from a taurine transporter knockout mouse (taut-/-) against osmotic shock and oxidative stress. Erythrocyte cell volume was estimated from forward scatter and breakdown of phosphatidylserine asymmetry was identified by determination of annexin binding using FACS analysis. Erythrocytes from taut-/- mice were compared to erythrocytes from wild type littermates (taut+/+). Plasma concentration and erythrocyte content of taurine was significantly lower in taut-/- than in taut+/+ mice, but the intraerythrocyte taurine concentration did not exceed the plasma concentration. Hyperosmotic shock (exposure to 700 mOsm) and oxidative stress (exposure to 0.1 mM tert-butyl-hydroperoxide) significantly decreased the cell volume and increased the number of annexin binding sites of erythrocytes from both, taut-/- and taut+/+ mice. However, decrease of cell volume and increase of annexin binding was significantly blunted in erythrocytes from taut-/- mice as compared to their taut+/+ littermates. Stimulation of erythropoiesis by prior hemorrhage did not abrogate the difference between taut+/+ and taut-/- erythrocytes. The present observations point to a decreased sensitivity of mature erythrocytes from taut-/- mice to osmotic shock and oxidative stress, rendering them more resistant to apoptosis.

Amino Acids↗

PubMed2003

Renal Ca2+ wasting, hyperabsorption, and reduced bone thickness in mice lacking TRPV5.

Ca2+ ions play a fundamental role in many cellular processes, and the extracellular concentration of Ca2+ is kept under strict control to allow the proper physiological functions to take place. The kidney, small intestine, and bone determine the Ca2+ flux to the extracellular Ca2+ pool in a concerted fashion. Transient receptor potential (TRP) cation channel subfamily V, members 5 and 6 (TRPV5 and TRPV6) have recently been postulated to be the molecular gatekeepers facilitating Ca2+ influx in these tissues and are members of the TRP family, which mediates diverse biological effects ranging from pain perception to male aggression. Genetic ablation of TRPV5 in the mouse allowed us to investigate the function of this novel Ca2+ channel in maintaining the Ca2+ balance. Here, we demonstrate that mice lacking TRPV5 display diminished active Ca2+ reabsorption despite enhanced vitamin D levels, causing severe hypercalciuria. In vivo micropuncture experiments demonstrated that Ca2+ reabsorption was malfunctioning within the early part of the distal convolution, exactly where TRPV5 is localized. In addition, compensatory hyperabsorption of dietary Ca2+ was measured in TRPV5 knockout mice. Furthermore, the knockout mice exhibited significant disturbances in bone structure, including reduced trabecular and cortical bone thickness. These data demonstrate the key function of TRPV5 in active Ca2+ reabsorption and its essential role in the Ca2+ homeostasis.

Absorption↗