Renal TRPathies

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Renal TRPathies Alexander Dietrich,* Vladimir Chubanov,† and Thomas Gudermann† *Institute of Pharmacology and Toxicology, School of Medicine, University of Marburg, Marburg, Germany; and † Walther-Straub-Institute of Pharmacology and Toxicology, University of Munich, Munich, Germany

ABSTRACT Many ion channels and transporters are involved in the filtration, secretion, and resorption of electrolytes by the kidney. In recent years, the superfamily of transient receptor potential (TRP) ion channels have received deserved attention because mutated TRP channels are linked to human kidney diseases. This review focuses on two TRP members—TRPC6 and TRPM6 —and their functions in the kidney. Gain-of-function mutations in TRPC6 are the cause for progressive kidney failure with urinary protein loss such as FSGS. Thus, TRPC6 is an essential signaling component in a functional slit diaphragm formed by podocytes around the glomerular capillaries. Loss-of-function mutations in TRPM6 are a molecular cause of hypomagnesemia with secondary hypocalcemia, suggesting that TRPM6 is critically involved in transcellular Mg2⫹ transport in the kidney. Here, we highlight how recent studies analyzing function and expression of these channels in the kidney improve our mechanistic understanding of TRP channel function in general and pave the way to new, promising therapeutic strategies to target kidney diseases such as FSGS and hypomagnesemia with secondary hypocalcemia. J Am Soc Nephrol 21: 736 –744, 2010. doi: 10.1681/ASN.2009090948

One key function of the kidneys is the ultrafiltration of plasma by glomeruli to dispose of metabolic end products, excess electrolytes, and water. A vast array of ion channels and transporters are critical for filtration, secretion, and resorption of electrolytes to maintain homeostasis. In recent years, investigations have focused on several members of the large transient receptor potential (TRP) family of ion channels, because mutations in genes encoding members of three different TRP ion channel subfamilies have been linked to human kidney diseases.1 Mutations in PKD1 (encoding TRPP1) and PKD2 (coding for TRPP2) occur at high frequency in individuals with autosomal dominant polycystic kidney disease.2,3 The latter mutations and the pathophysiology of polycystic kidney disease are not discussed further in this overview because the topic has been covered by numerous insightful review articles.4 –7 Missense and nonsense mutations in 736

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the gene coding for TRPC6 segregate with autosomal dominant FSGS, a kidney disease that leads to progressive renal failure.8,9 Loss-of-function mutations in TRPM6 are also associated with hypomagnesemia with secondary hypocalcemia (HSH), a rare autosomal recessive disorder.10 –12 The involvement of TRP channel mutations in hereditary kidney disease has shed new light on the molecular pathogenesis of renal failure and significantly enhanced our appreciation of the physiologic roles of TRP channels on tubular function. In this review, we focus exclusively on TRPC6 and TRPM6.

TRPC6 AND PODOCYTE FUNCTION

TRPC6 is a nonselective cation channel and one of the seven members of the clas-

sical transient receptor potential (TRPC) family, which can be divided into subfamilies on the basis of amino acid similarity. Whereas TRPC1 and TRPC2 are almost unique, TRPC4 and TRPC5 share approximately 64% amino acid identity. TRPC3, TRPC6, and TRPC7 form a structural and functional subfamily displaying 65 to 78% identity at the amino acid level and share a common activator, diacylglycerol (DAG).13 DAG is produced by phospholipase C isozymes activated after agonist binding to appropriate receptors, such as the interaction of angiotensin II (AngII) with AT1 receptors. Like all TRPC family members, TRPC6 harbors an invariant sequence, the TRP box (containing the amino acid sequence EWKFAR), in its C-terminal tail as well as three ankyrin repeats in the N-terminus (Figure 1, A and B). The predicted transmembrane topology is similar to that of other TRP channels with intracellular N- and C-termini, six membrane-spanning helices (S1 through S6), and a presumed pore-forming loop (P) between S5 and S6 (Figure 1, A and B). As deduced from Northern blot analyses, TRPC6 channels are most prominently expressed in lung tissues,14 where they Published online ahead of print. Publication date available at www.jasn.org. A.D. and V.C. contributed equally to this work. Correspondence: Dr. Thomas Gudermann, Walther-Straub-Institute of Pharmacology and Toxicology, University of Munich, Goethestrasse 33, D-80336 Munich, Germany. Phone: ⫹49-89-218075700; Fax: ⫹49-89-2180-75701; E-mail: thomas. [email protected] Copyright 䊚 2010 by the American Society of Nephrology

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Figure 1. Structural features of TRPC6 and its function in podocytes. (A) Topology of TRPC6 in the plasma membrane (PM) indicating transmembrane regions (S1 through S6) and the predicted pore domain (P). Two glycosylated sites in TRPC6 are indicated by covalently bound carbohydrates (gray).105 (B) Localization of the identified mutations in patients with nephrotic syndromes. A, ankyrin repeat; L, lipid/trafficking domain; CC, predicted coiled-coil domain; EWKFAR, conserved TRP box motif. Amino acid changes are indicated by the single-letter code and a number for the exact position in the protein; *a stop codon (truncation mutant). (C) Podocyte foot process with important signaling molecules. Mechanical activation of podocin or receptor-stimulated activation of phospholipase C-␧ (PLC␧) activates TRPC6 channels, leading to actin (red line) reorganization and subsequent closure of the slit diaphragm by homophilic nephrin interactions (arrows). See text for more details. PIP2, phosphatidylinositol-3,4-bisphosphate; GBM, glomerular basement membrane.

play an important role in vascular and pulmonary smooth muscle cells.15 In the kidney, TRPC6 and TRPC3 are detected along the glomerulus and the collecting duct.16 Heteromeric complexes comprising TRPC3 and TRPC6 in podocytes co-localize with aquaporin 2 in principal cells of the collecting duct.17 In polarized cultures of M1 and IMCD-3 collecting duct cells, however, TRPC3 localizes exclusively to the apical domain, whereas TRPC6 is on both basolateral and apical membranes.18 Native TRPC3/6 heteromers are also found in MDCK cells.19 Sclerotic lesions in the subtotal of renal glomeruli characterize FSGS. In six families with hereditary forms of FSGS, two research groups independently identified gain-of-function mutations in the TRPC6 channel (Figure 1C) leading to enhanced calcium influx (P112Q8) or inJ Am Soc Nephrol 21: 736 –744, 2010

creased current amplitudes in electrophysiological recordings of expressed ion channels (R895C and E897K9). TRPC6 expression in the kidney localizes to glomeruli and tubuli8 as well as podocytes.9 Three other mutations identified by Reiser et al.20 (N143S, S270T, and K874*) do affect current amplitudes but allow channels to stay open longer than wildtype TRPC6 channels. Moreover, channel density at the plasma membrane is significantly higher in HEK293 cells expressing the P112Q mutant. Recently, a seventh mutation (Q889K) was found in 31 Chinese pedigrees with late-onset FSGS.21 HEK293 cells expressing the mutant channel protein show significantly higher Ca2⫹ influx after stimulation by a membrane-permeable analogue of DAG—an observation attributable to a significantly higher level of expression of

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the mutant protein. TRPC6 mutation analysis in 130 Spanish patients with FSGS identified three additional, as yet functionally uncharacterized TRPC6 missense mutations, two in the N-terminus close to the ankyrin repeats (G109S and N125S) and a third one adjacent to the TRP domain (L780P).22 Most notably, TRPC6 mutations are also described in children and adults with nonfamilial FSGS. An 11th missense mutation (M132T) that shows a mean inward calcium current 10-fold larger than that of wild-type TRPC6 was recently identified in childhood FSGS.23 In aggregate, the mutations described so far indicate a frequency of 6% of TRPC6 mutations in familial FSGS and approximately 2% in sporadic cases.22 All mutations map to the terminal domains of the TRPC6 protein (see Figure 1). Six N-terminal missense mutations (G109S, P112Q, M132T, N125S, N143S, and S270T) locate in or near ankyrin repeats and an adjacent lipid/trafficking domain. The ankyrin domains are responsible for self-association of TRPC homomers,24 whereas the lipid-binding domain binds DAG and participates in the translocation of the channel to the plasma membrane.25 Whereas the L780P mutation is located near to the EWKFAR motif conserved in all TRP channels, four additional mutations (K874*, Q889K, R895C, and E897K) map to a predicted coiled-coil domain at the C-terminus. It is tempting to speculate that gain-of-function phenotypes occur after more efficient multimerization and/or translocation to the plasma membrane or impaired ion channel endocytosis, as well as by blocking the binding of an inhibitory protein to a predicted Cterminal coiled-coil domain; however, so far, there are no hard experimental data to support any of these speculations. Other proteins mutated in patients with FSGS or related diseases include nephrin, podocin, ␣4-actinin, phospholipase C-␧, laminin ␤2, and others.26 Most of these mutations lead to earlyonset disease,27 underscoring their indispensable role in filtration at the slit diaphragm. The TRPC6 protein directly interacts with key structural and signalRenal TRPathies

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ing proteins of the podocyte, podocin and nephrin. The podocin homologue mec-2 contributes to mechanosensation in Caenorhabditis elegans by linking mechanosensitive ion channels to the cytoskeleton; therefore, podocin might detect mechanical forces exerted by the glomerular filtration process, resulting in TRPC6 activation. Accordingly, heterologously expressed podocin regulates TRPC6 activity in a cholesterol-dependent manner.28 Moreover, mutations in the podocin gene give rise to hereditary nephrotic syndromes in humans, compatible with an important role of podocin as a mechanosensor at the slit diaphragm. The recently proposed mechanosensitivity of TRPC6 channels29 is not detectable at physiologically relevant pressures of ⬍80 mmHg,30 and three additional, independent studies failed to demonstrate that TRPC6 per se is mechanosensitive.31–33 The second TRPC6-interacting protein, nephrin, is an essential constituent of the slit diaphragm contributing to actin reorganization in podocytes by engaging a phosphoinositide 3-kinase pathway34 subsequent to phosphorylation by the Src family protein tyrosine kinase Fyn.35 The functional relevance of TRPC6 phosphorylation by Fyn36 was called into question on the basis of functional analyses of TRPC6 phosphorylation site mutants.37 Disruption of the slit diaphragm architecture in nephrin-deficient mice leads to overexpression and mislocalization of TRPC6 in podocytes9 and supports the concept that TRPC6 integrates into an organized signaling complex in podocytes with nephrin, podocin, and probably AT1 AngII receptors.1 Because TRPC6 is a Ca2⫹-permeable ion channel, one may assume that Ca2⫹ influx through activated channels induces actin reorganization, leading to a more flattened cell shape and a closure of the slit diaphragm mediated by the homophilic interaction of nephrin molecules (Figure 1C). Moreover, lossof-function mutations in phospholipase C-␧, a central signaling molecule that cleaves phosphatidylinositol-3,4bisphosphate to generate DAG, a potent lipid activator of TRPC6, in re738

sponse to receptor stimulation were identified by screening patients with early-onset nephrotic syndromes such as FSGS and diffuse mesangial sclerosis.38 In a mechanistic model, elevated BP with increased levels of AngII or increased shear stress engage AT1 receptors, activating TRPC6 channels subsequently to close the slit diaphragm; however, at first glance, the lack of an overt renal phenotype in TRPC6⫺/⫺ mice does not conform to the aforementioned model. However, the closely related TRPC channel, TRPC3, is upregulated in vascular and airway smooth muscle cells.39,40 Because endogenous TRPC3 expression in podocytes has been demonstrated,17,41 compensatory upregulation of TRPC3 is an intriguing possibility to explain the lack of phenotype in mice and the absence of TRPC6 loss-of-function mutations in patients with FSGS. An essential role of TRPC channels has been invoked in cardiac hypertrophy and remodeling. Ca2⫹-mediated activation of calcineurin induces the hypertrophic response by downstream nuclear factor of activated T cells (NFAT) transcription factors, which are necessary and sufficient for the induction of cardiac hypertrophy.42 Interestingly, similar mechanisms operate in cultured podocytes heterologously expressing three TRPC6 gain-of-function mutations (P112Q, R895C, and E897K). All three channel mutants result in enhanced basal NFAT-mediated transcription in several cell lines including cultured podocytes.43 Although the genes transcribed after activation of NFAT in podocytes are still unknown, a similar scenario to the one worked out for the heart is conceivable. It should not go unnoticed, however, that increased levels of TRPC6 expression in cultured podocytes result in a disruption of the actin cytoskeleton, and in vivo delivery of cDNA encoding TRPC6 into mice induces proteinuria.44 Moreover, disruption of the ultrafiltration process at the slit diaphragm might also be induced by Ca2⫹ overload in podocytes, leading to apoptosis. Although experimental data stringently confirming these hypotheses are lacking,45 AngII induces apoptosis in rat podocytes.46

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In summary, little is known about the exact role of TRPC6 in podocytes or the ultrafiltration process. Nevertheless, our understanding of the molecular processes governing podocyte function is increasing and may lead to the identification of therapeutic strategies to treat FSGS and related diseases.

ROLE OF TRPM6 CHANNELS IN RENAL MAGNESIUM HOMEOSTASIS

Divalent cation-selective outwardly rectifying currents, which are induced upon removal of intracellular Mg2⫹, are a general feature of various invertebrate cells and have been identified in all mammalian cells examined so far.47–53 These currents are referred to as magnesiuminhibited currents (MIC) or magnesium nucleotide-regulated metal ion currents (MagNuM).47– 49,54,55 TRPM6 and TRPM7 (melastatin-related members of the TRP gene family) were subsequently defined as molecular correlates of MIC/MagNuM channels. The current scientific literature reflects a broad spectrum of speculations on the physiologic roles of TRPM6 and TRPM7; however, compelling initial information about the physiologic relevance of TRPM6 and TRPM7 was obtained by clinical and molecular studies on a hereditary disorder associated with renal Mg2⫹ wasting. Mutations in the human TRPM6 gene give rise to autosomal recessive HSH.10,56 Here, we describe the latest progress made toward the molecular characterization of TRPM6/7 in light of their possible role in renal magnesium handling. Other aspects of TRPM channels are addressed in a number of excellent review articles.7,12,57– 64 A few years ago, two independent groups showed that loss-of-function mutations in the human TRPM6 gene are the molecular cause of HSH.10,56 HSH is an autosomal recessive disease that manifests in early infancy with generalized convulsions or symptoms of increased neuromuscular excitability including muscle spasms and tetJ Am Soc Nephrol 21: 736 –744, 2010

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Figure 2. Architecture of TRPM6/M7 kinase-linked channel complexes. (A) Schematic domain topology of TRPM6 channels. A hexahelical channel segment of TRPM6 (1 through 6) is fused to a C-terminal serine/threonine protein kinase domain (Kinase). Positions of five missense mutations identified in patients with HSH66,77,78 are indicated by red dots. (B) Pore-forming segment of heterotetrameric channel complexes formed by TRPM6 and TRPM7. A short stretch between transmembrane helices 5 and 6 contains a putative pore-forming loop; four subunits of the tetramer are thought to contribute to a common channel pore. Four negatively charged glutamates (⫺) form a common highaffinity biding site for permeant ions such as Mg2⫹ and Ca2⫹ (⫹⫹).73

any.10,12,56,65,66 Clinical examination at the time of manifestation typically reveals very low Mg2⫹ (0.1 to 0.3 mM) and low Ca2⫹ (1.0 to 1.6 mM) serum concentrations compared with normal (0.7 to 1.1 mM [Mg2⫹] and 2.2 to 2.9 mM [Ca2⫹]). Of note, patients with HSH exhibit a high fractional excretion of Mg2⫹ of approximately 3%, whereas healthy individuals preserve Mg2⫹ by reducing fractional excretion to ⬍1% during Mg2⫹ deficiency, thus indicating that renal Mg2⫹ handling is primarily affected in individuals with HSH. Hypocalcemia seems to be caused by diminished parathyroid hormone release as a result of profound hypomagnesemia.56,67,68 Relief of HSH symptoms is achieved by administration of high dosages of Mg2⫹. Despite this treatment, serum Mg2⫹ levels remain in the subnormal range (approximately 0.5 mM). Delay in diagnosis and therapy results in permanent neurologic deficits or even fatality.10,12,56,65,66 TRPM6 belongs to the TRPM family of cation channels whose members exhibit a marked diversity in ion selectivity and activation mechanisms.60,62,69 –74 TRPM6 displays approximately 50% amino acid sequence identity with its homologous J Am Soc Nephrol 21: 736 –744, 2010

family member, TRPM7.10,11,47,50,56 Both TRPM6 and TRPM7 encode cation channel subunits characterized by the covalent linkage to a C-terminal serine/threonine protein kinase domain resembling elongation factor 2 kinase and other ␣-kinases (Figure 2A).75 It is generally assumed that the architecture of the pore-forming segment in TRPM channels has significant homology to tetrameric voltage-gated K⫹ channel complexes: A short stretch between transmembrane helices 5 and 6 contains a hydrophobic pore helix followed by a pore loop; the loops of all four subunits of the tetramer are thought to contribute to a common selectivity filter (Figure 2B). The human TRPM6 gene comprises 39 exons and encodes multiple mRNA isoforms. For instance, alternative 5⬘ exons of the gene can be spliced to a common second exon, suggesting the TRPM6 promoter governs mRNA expression by means of alternative transcription start sites.11,76 Furthermore, several isoforms encode TRPM6 kinases because the alternatively spliced transcripts lack exons coding for the transmembrane segment of the channel.11,76 Functional consequences of the naturally occurring TRPM6 mutations include introduction of frame shifts, stop codons,

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or disruption of exon splice sites.66,77,78 Only five missense mutations have been identified so far (Figure 2A)66,77,78; their impact on TRPM6 function is discussed next. The pathophysiologic connection between hypomagnesemia and mutations in TRPM6 is mainly deduced from our current view on Mg2⫹ homeostasis.12,65,79 – 83 The total Mg2⫹ concentration in the majority of cells is between 10 and 20 mM. Intracellular Mg2⫹ is mostly bound to phosphonucleotides, phospholipids, and proteins. The free cellular Mg2⫹ concentration ([Mg2⫹]i) is estimated to be in the range of 0.5 to 1.0 mM, whereas the extracellular concentration of Mg2⫹ is between 0.9 and 1.0 mM, approximately 50% of which is bound to albumin and other molecules. Thus, mammalian cells lack a substantial transmembrane chemical gradient for ionized Mg2⫹. It is assumed, therefore, that the entry of Mg2⫹ into the cell is primarily driven by the electrical gradient across the plasma membrane.12,65,79 – 83 Physiologic studies identify two different transport systems for Mg2⫹ in the kidney and intestinal epithelia: An active transcellular and passive paracellular transport pathway.65,83,84 The saturable transcellular uptake consists of apical entry into epithelial cells most likely through Mg2⫹-selective ion channels and a putative basolateral extrusion step, which may couple Mg2⫹ export to Na⫹ influx (Figure 3). In the kidney, these two different transport pathways are arranged sequentially along the nephron.65,83,84 Most of the filtered Mg2⫹ is resorbed in the thick ascending limb of Henle’s loop by a passive paracellular route driven by positive transepithelial voltage. Tight junctions containing claudin-19 (CLDN19) are pivotal cellular components intimately involved in this paracellular transport.85 Only 5 to 10% of the filtered Mg2⫹ is resorbed in the distal convoluted tubule (DCT), which resorbs Mg2⫹ solely by the transcellular route. Unlike upstream nephron segments, the DCT has a negative transepithelial voltage and high epithelial resistance (Figure 3), and no Mg2⫹ resorption is detected in more disRenal TRPathies

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Figure 3. Schematic model depicting the role of TRPM6/7 channel complexes for transcellular Mg2⫹ transport in the DCT. Note that the DCT segment is characterized by a negative transepithelial voltage and lacks a substantial transmembrane chemical gradient for ionized Mg2⫹. For further explanation, see text.

tal nephron segments; therefore, the DCT determines the final urinary [Mg2⫹].64,65,83,86 As already alluded to, an electrical gradient is the primary driving force for Mg2⫹ along either the transcellular or the paracellular route. In line with this notion, numerous hormones, drugs, and certain pathophysiologic states that affect the membrane potential of the apical or basolateral plasma membrane of the DCT have a strong impact on net Mg2⫹ resorption.7,12,83,87,88 Against this background, it is reasonable to test whether TRPM6 is enriched in the DCT. In fact, by transcript copy number and in situ hybridization, pronounced expression of TRPM6 transcripts is present in the DCT.10,11,65 Subsequently, Schlingmann and colleagues10,65 postulated that TRPM6 represents the apical Mg2⫹-permeable ion channel responsible for Mg2⫹ uptake by DCT cells. More recently, immunohistochemistry of mouse kidney sections confirmed TRPM6 is present on the apical cell border along the DCT.89 On the contrary, mRNA encoding TRPM7 is detectable at a similar level in all nephron segments.11,65 The latter observation is not too surprising, because previous patch-clamp experiments and expression studies revealed that TRPM7 is ubiquitously present in all cell types tested so far.47–50,72,90 Thus, both ion 740

channels are coexpressed in the same nephron segment, but, in terms of function, TRPM6 is nonredundant. Conflicting findings are reported concerning functional characteristics of TRPM6 in heterologous cell systems. According to Voets et al.89 and Li et al.,90 recombinant TRPM6 expressed in HEK293 or CHO cells forms homo-oligomeric channels with biophysical characteristics similar to those of TRPM7. In particular, TRPM6 is somewhat more permeable to Mg2⫹ than to Ca2⫹ and, like TRPM7, sensitive to intracellular Mg2⫹ levels.89,90 In addition, TRPM6 channel activity is negatively regulated by receptor of activated protein kinase C 1, the repressor of estrogen receptor activity, and ATP through binding sites located in the TRPM6 kinase domain.91–93 An EGF receptor– dependent pathway regulates TRPM6 trafficking to the cell surface.94 Interestingly, EGF was identified as a magnesiotropic hormone, because a missense mutation in the EGF gene underlies isolated autosomal recessive renal hypomagnesemia (IRH).95 Groenestege et al.95 suggested that reduced TRPM6 function as a result of impaired trafficking to the plasma membrane is responsible for the IRH phenotype. It should be noted, however, that, unlike patients with HSH, patients with IRH showed normal serum concen-

Journal of the American Society of Nephrology

trations of Ca2⫹ and parathyroid hormone,95 illustrating that the pathophysiology of IRH differs from that of HSH, which is caused by mutations in TRPM6. In contrast to these studies, other studies11,77,96 provided biophysical, biochemical, and cellular evidence that TRPM6 displays features remarkably different from those of TRPM7. In particular, TRPM6 expressed in HEK293 cells, Xenopus oocytes, or DT40 lymphocytes96,97 does not efficiently form homomultimeric channel complexes in the plasma membrane and required TRPM7 for co-targeting to the cell surface. In the hetero-multimers formed, the TRPM6 kinase domain cross-phosphorylates TRPM7 but not vice versa.96 TRPM6/7 hetero-oligomeric channels are distinguishable in terms of singlechannel conductance, divalent cation permeability, and pH sensitivity from homo-multimers.90 TRPM7 is expressed ubiquitously, whereas TRPM6 expression is restricted to a few cell types, such as DCT cells.10,11,47,56 Furthermore, attempts to record native currents mediated solely by TRPM6 homo-oligomers have not been successful.90 In this vein, the specific and efficient heteromeric assembly of TRPM6 and TRPM7 may reflect the intrinsic mode of TRPM6 function as a subunit of TRPM6/7 complexes. Accordingly, both TRPM6 and TRPM7 contribute to transcellular Mg2⫹ transport in the DCT (Figure 3). Two scenarios emerge to explain the pathophysiologic consequences of lossof-function mutations in TRPM6. First, TRPM6/7 hetero-oligomers are the main mediators of MIC/MagNuM currents, and TRPM7 alone can only partially restore proper DCT function in terms of Mg2⫹ resorption. Second, a specific, still unidentified functional characteristic of heteromeric TRPM6/7 complexes is essential for DCT cell function and cannot be conferred by TRPM7 homo-multimers (Figure 3). The majority of HSH mutations in the TRPM6 gene most likely result in the complete lack of protein expression, thereby offering a straightforward explanation for the loss-of-function phenoJ Am Soc Nephrol 21: 736 –744, 2010

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type. So far, only five point mutations in TRPM6 are known (Figure 2A). Four of them are located in the N-terminus of the channel protein, suggesting a critical role of this domain for channel function. In fact, the TRPM6S141L channel mutant is unable to associate with TRPM7.11 Consistently, the introduction of the homologous missense mutation into TRPM7 also affects ion channel assembly. More recently, a new missense mutation, P1017R, located in the putative pore-forming region of TRPM6 (Figure 2A) was characterized.78 This mutation affects neither expression of the TRPM6 protein nor its co-assembly with TRPM7 but impairs channel activity of TRPM6/7 complexes by dominant negative suppression. The effect exerted by TRPM6P1017R strongly supports the notion that both subunits contribute to a common channel pore in TRPM6/7 complexes (Figure 2B). Thus, one may conclude that considering the ion channel and kinase moieties of TRPM6, suppression of cation fluxes by TRPM6/7 complexes is sufficient for the development of HSH. Hence, these observations provide invaluable information about the poorly understood contribution of TRPM6 channel and kinase activities to the HSH phenotype. Overall, both of these studies suggest that TRPM7 is critically involved in transcellular Mg2⫹ transport and that genetic disruption of TRPM7 would have a much stronger impact on renal Mg2⫹ handling than inactivation of TRPM6. Thus, it would be interesting to investigate whether TRPM7⫹/⫺ mice98 display hypomagnesemia. Two genetic model organisms, mouse and zebrafish, have been used to gain deeper insight into the role of TRPM7 in vivo.98,99 Thus, a set of loss-of-function mutations in the TRPM7 gene cause complex changes in the development of zebrafish.99 Mutant larvae exhibit neural crest-derived melanophore deficiencies and temporary touch unresponsiveness and die 14 to 16 days after fertilization. Interestingly, Mg2⫹ supplementation partially rescues melanophore development, whereas Ca2⫹ partially restores J Am Soc Nephrol 21: 736 –744, 2010

both melanophore development and touch responsiveness, suggesting that mutations in TRPM7 affect the homeostasis of both cations in zebrafish. As in zebrafish, TRPM7 is essential for the embryonic development of mice: Embryos deficient in TRPM7 die at the preimplantation stage for unknown reasons.98 Conditional deletion of TRPM7 in the T cell lineage disrupted thymopoiesis, resulting in progressive depletion of thymic medullary cells. TRPM7-deficient thymocytes exhibit a dysregulated synthesis of various growth factors; however, unlike DT40 lymphocytes, thymocytes from TRPM7-deficient mice showed normal intracellular Mg2⫹ levels. Therefore, the authors conclude that TRPM7 is not essential for Mg2⫹ uptake by mouse thymocytes.98 It should be mentioned, however, that genetic interactions of TRPM7 with other proteins are still poorly understood. Thus, it is imaginable that a particular cellular phenotype of TRPM7-deficient cells may critically depend on the expression profile of other Mg2⫹-permeable ion channels and Mg2⫹ transporters such as MagT1 and TUSC3.100 In keeping with this notion, Mg2⫹ deficiency in DT40 cells with a disrupted TRPM7 gene is rescued by overexpression of the plasma membrane Mg2⫹ transporter SLC41A2 or constitutively active phosphoinositide 3-kinase.101,102 The recent description of a TRPM6deficient mouse model adds yet another level of complexity.103 The absence of TRPM6 gives rise to a different phenotype in mice than in humans. In contrast to previous expectations, the majority of TRPM6⫺/⫺ mice die at approximately day 12.5. Those that survive display massive neural tube closure defects.103 Interestingly, plasma Mg2⫹ levels are lower in TRPM6⫹/⫺ as compared with TRPM6⫹/⫹ mice. In contrast to HSH, high-Mg2⫹ diet does not prevent mortality in TRPM6-null embryos. These findings indicate a critical role of TRPM6 in mouse development. With regard to the human situation, it will be enlightening to reinvestigate HSH pedigrees for fetal wastage and developmental abnormalities.

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CONCLUSIONS

In the past few years, TRP channels have emerged as central players in human renal physiology, and mutations in these proteins are associated with frequently occurring kidney diseases as well as other pathologies.104 As more information on the in vivo role of TRP channels in suitable animal models and additional clinical data from patients carrying mutations in TRP channel genes become available, our knowledge of the role of TRP channels in renal pathophysiology will expand considerably. Further progress in this field will improve our mechanistic understanding of TRP channel function in general and may help in identification of novel therapeutic targets.

ACKNOWLEDGMENTS Work in the authors’ laboratories is supported by research project grants from the Deutsche Forschungsgemeinschaft (A.D., T.G., and V.C.), the Wissenschaftliches Herausgeberkollegium der Mu¨nchener Medizinischen Wochenschrift Stiftung (V.C.), and the Fritz-Thyssen-Stiftung (A.D. and T.G.).

DISCLOSURES None.

REFERENCES 1. Gudermann T: A new TRP to kidney disease. Nat Genet 37: 663– 664, 2005 2. Wu G, Somlo S: Molecular genetics and mechanism of autosomal dominant polycystic kidney disease. Mol Genet Metab 69: 1–15, 2000 3. Chang MY, Ong AC: Autosomal dominant polycystic kidney disease: Recent advances in pathogenesis and treatment. Nephron Physiol 108: 1–7, 2008 4. Wilson PD: Mouse models of polycystic kidney disease. Curr Top Dev Biol 84: 311– 350, 2008 5. Patel V, Chowdhury R, Igarashi P: Advances in the pathogenesis and treatment of polycystic kidney disease. Curr Opin Nephrol Hypertens 18: 99 –106, 2009 6. Harris PC, Torres VE: Polycystic kidney disease. Annu Rev Med 60: 321–337, 2009

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