Review
Physiology
Il Hwan Oh, Chor Ho Jo, Sua Kim, Sungsin Jo, Sungjin Chung, Gheun-Ho Kim
Summary: The study revealed that metabolic acidosis-induced hypercalciuria and hypermagnesiuria are due to the down-regulation of claudin-16 and claudin-19 in the thick ascending limb via the calcium-sensing receptor and can be reversed by the calcium-sensing receptor antagonist. These findings contribute to understanding the regulatory role of paracellular tight junction proteins in the thick ascending limb.
AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY
(2021)
Review
Multidisciplinary Sciences
R. Todd Alexander, Henrik Dimke
Summary: Calcium and magnesium, as the most abundant divalent cations in the body, are regulated by intestinal absorption, kidney reabsorption, and bone storage and exchange. The majority of filtered divalent cations are reabsorbed through paracellular pathways in the proximal tubule and thick ascending limb of the loop of Henle. Calcium is mostly reabsorbed in the proximal tubule, while magnesium is mostly reabsorbed in the thick ascending limb.
ANNALS OF THE NEW YORK ACADEMY OF SCIENCES
(2022)
Article
Multidisciplinary Sciences
Megan R. Beggs, Kennedi Young, Wanling Pan, Debbie D. O'Neill, Matthew Saurette, Allein Plain, Juraj Rievaj, Michael R. Doschak, Emmanuelle Cordat, Henrik Dimke, R. Todd Alexander
Summary: Calcium homeostasis is maintained through coordination between intestinal absorption, renal reabsorption, and bone remodeling with tight-junction proteins called claudins playing a crucial role. Claudins-2 and -12 form independent Ca2+ permeable pores in renal and colonic epithelia, with either one sufficient to maintain Ca2+ balance. Deletion of both claudins leads to reduced intestinal Ca2+ absorption, higher urinary Ca2+ wasting, hypocalcemia, and reduced bone mineral density compared to single-null animals.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Article
Multidisciplinary Sciences
Caroline Hempel, Rita Rosenthal, Anja Fromm, Susanne M. Krug, Michael Fromm, Dorothee Gunzel, Joerg Piontek
Summary: This study analyzed the structural and functional differences between claudin-15 and claudin-10b cation channels and identified several mutants that affect ion permeability and pore diameter. Furthermore, the study revealed that the charge at the W63/K64 position has an impact on the assembly and properties of claudin-10b channels but not claudin-15 channels.
ANNALS OF THE NEW YORK ACADEMY OF SCIENCES
(2022)
Review
Biochemistry & Molecular Biology
Ashley Monaco, Ben Ovryn, Josephine Axis, Kurt Amsler
Summary: The paracellular permeability in epithelial cells involves both a Pore Pathway for small ions and solutes, and a Leak Pathway for larger solutes. While the Pore Pathway is better understood, the proteins and mechanism behind the Leak Pathway remain unresolved and controversial. Further research is needed to clarify the molecular basis and regulation of the Leak Pathway.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Multidisciplinary Sciences
Henrik Dimke, Camille Griveau, Wung-Man Evelyne Ling, Gaelle Brideau, Lydie Cheval, Pravina Muthan, Dominik Mueller, Amr Al-Shebel, Pascal Houillier, Caroline Prot-Bertoye
Summary: The kidney plays a critical role in maintaining mineral balance in the body. Dysregulation of calcium and magnesium reabsorption in the renal tubules can lead to familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC), which is characterized by excessive wasting of calcium and magnesium. This study investigated the localization of claudin-19 (CLDN19), a protein involved in mineral reabsorption, in the kidneys and found that it is primarily located in the basolateral membrane of the renal tubules. Additionally, the study showed that CLDN19 interacts with claudin-16 (CLDN16) to regulate permeability in the tubules. These findings provide insights into the pathophysiology of FHHNC and highlight the importance of CLDN19 in maintaining mineral homeostasis in the kidney.
ANNALS OF THE NEW YORK ACADEMY OF SCIENCES
(2023)
Article
Multidisciplinary Sciences
Catarina Quintanova, Nina Himmerkus, Samuel L. Svendsen, Otto von Schwerdtner, Cosima Merkel, Lennart Pinckert, Kerim Mutig, Tilman Breiderhoff, Dominik Mueller, Dorothee Guenzel, Markus Bleich
Summary: Claudin-10b is an important component of the tight junction and allows paracellular sodium transport in the thick ascending limb of Henle's loop. It colocalizes with the basolateral Na+-K+ ATPase and the Cl- channel subunit barttin, and its absence increases the accessibility of the basolateral extracellular space to certain substances. Electron microscopy reveals a widening of basolateral membrane infoldings in the absence of Claudin-10b. These findings suggest that Claudin-10b may shape neighboring membrane invaginations through trans interaction, thereby stabilizing and facilitating high-flux salt transport.
ANNALS OF THE NEW YORK ACADEMY OF SCIENCES
(2022)
Article
Biochemistry & Molecular Biology
Sebastian Sewerin, Jorg Piontek, Ria Schonauer, Sonja Grunewald, Angelika Rauch, Steffen Neuber, Carsten Bergmann, Dorothee Gunzel, Jan Halbritter
Summary: This study investigated the molecular basis and phenotypic consequences of a CLDN10 gene variant, which disrupts the assembly of tight junction (TJ) strands. The mutant proteins compromised the function of TJ and exhibited tissue-specific insertion into TJs.
Article
Biochemistry & Molecular Biology
Santhosh Kumar Nagarajan, Stanislav Klein, Bita Sokhandan Fadakar, Joerg Piontek
Summary: Claudin proteins are crucial for regulating paracellular permeability in tight junctions. The architectural models of claudin-10b and claudin-15 suggest an octameric-interlocked-barrels structure, which contributes to their functional differences in ion and water permeability.
COMPUTATIONAL AND STRUCTURAL BIOTECHNOLOGY JOURNAL
(2023)
Review
Biochemistry & Molecular Biology
Rina Fujiwara-Tani, Shiori Mori, Ruiko Ogata, Rika Sasaki, Ayaka Ikemoto, Shingo Kishi, Masuo Kondoh, Hiroki Kuniyasu
Summary: CLDN4 is a crucial component of tight junctions in epithelial cells and is overexpressed in many epithelial malignancies. Changes in CLDN4 expression are associated with epigenetic factors, inflammation, and growth factor signaling. CLDN4 plays a role in maintaining the tumor microenvironment and acts as a barrier to anticancer drug entry.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Physiology
Dorothee Guenzel
Summary: The concept of solvent drag involves the frictional coupling between water and solutes in the same pore for transport. It has been applied to transport processes across cell membranes and along the paracellular pathway. Water-driven solute transport has been proposed as the major mechanism for absorption in the small intestine and reabsorption in the renal proximal tubule. However, the discovery of aquaporins and the claudin protein family has led to a reassessment of the solvent drag concept for transepithelial water and solute transport.
PFLUGERS ARCHIV-EUROPEAN JOURNAL OF PHYSIOLOGY
(2023)
Article
Physiology
Andree-Anne Marcoux, Laurence E. Tremblay, Samira Slimani, Marie-Jeanne Fiola, Fabrice Mac-Way, Ludwig Haydock, Alexandre P. Garneau, Paul Isenring
Summary: The loop of Henle plays important physiological roles in regulating extracellular fluid volume, blood pressure, ion balance, urinary concentration, and tubuloglomerular feedback. Recent studies have also highlighted its role in the renal-sparing effect of SGLT2 inhibitors.
COMPREHENSIVE PHYSIOLOGY
(2022)
Article
Food Science & Technology
Yunika Mayangsari, Mayu Okudaira, Chinatsu Mano, Yuki Tanaka, Osamu Ueda, Tomohiro Sakuta, Yoshiharu Suzuki, Yoshinari Yamamoto, Takuya Suzuki
Summary: Research showed that DMF can enhance intestinal TJ barrier integrity by increasing the expression of occludin and claudin-1, while reducing the expression of claudin-2. This regulation involves the induction of occludin protein translation via mTOR and silencing Cldn2 mRNA via miR-16-5p.
JOURNAL OF FUNCTIONAL FOODS
(2021)
Review
Multidisciplinary Sciences
Pascal Houillier, Loic Lievre, Marguerite Hureaux, Caroline Prot-Bertoye
Summary: Magnesium is crucial for many biological processes, including energy release. Paracellular transport is essential for magnesium homeostasis, and pathogenic variants in CLDN genes have been found to disturb this process. CLDN16 or CLDN19 loss of function leads to familial hypomagnesemia, while pathogenic CLDN10 variants cause HELIX syndrome, characterized by renal loss of sodium chloride and hypermagnesemia. This review summarizes the current knowledge of paracellular magnesium permeability and outlines some unresolved questions.
ANNALS OF THE NEW YORK ACADEMY OF SCIENCES
(2023)
Article
Physiology
Evans O. Asowata, Oluwatobi Olusanya, Kaoutar Abaakil, Havovi Chichger, Surjit K. S. Srai, Robert J. Unwin, Joanne Marks
Summary: The study found that iron deficiency increases calcium absorption in the duodenum but has no impact in the jejunum and ileum. Phosphate absorption is significantly inhibited in the duodenum and to a lesser extent the jejunum, while remaining unchanged in the ileum. These changes are associated with altered levels of claudins and no changes in hormonal regulators.
Article
Biochemistry & Molecular Biology
Duygu Elif Yilmaz, Karin Kirschner, Hasan Demirci, Nina Himmerkus, Sebastian Bachmann, Kerim Mutig
Summary: CsA-induced ER stress and pro-apoptotic UPR aggravate its nephrotoxicity, while pharmacological modulation of UPR has the potential to alleviate the renal side effects of CsA.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2022)
Article
Multidisciplinary Sciences
Markus M. Rinschen, Oleg Palygin, Ashraf El-Meanawy, Xavier Domingo-Almenara, Amelia Palermo, Lashodya Dissanayake, Daria Golosova, Michael A. Schafroth, Carlos Guijas, Fatih Demir, Johannes Jaegers, Megan L. Gliozzi, Jingchuan Xue, Martin Hoehne, Thomas Benzing, Bernard P. Kok, Enrique Saez, Markus Bleich, Nina Himmerkus, Ora A. Weisz, Benjamin F. Cravatt, Marcus Krueger, H. Paul Benton, Gary Siuzdak, Alexander Staruschenko
Summary: This study used isotope-guided metabolomics to investigate the metabolism of lysine in hypertension and found that lysine administration can protect the kidneys from hypertensive kidney damage.
NATURE COMMUNICATIONS
(2022)
Article
Multidisciplinary Sciences
Catarina Quintanova, Nina Himmerkus, Samuel L. Svendsen, Otto von Schwerdtner, Cosima Merkel, Lennart Pinckert, Kerim Mutig, Tilman Breiderhoff, Dominik Mueller, Dorothee Guenzel, Markus Bleich
Summary: Claudin-10b is an important component of the tight junction and allows paracellular sodium transport in the thick ascending limb of Henle's loop. It colocalizes with the basolateral Na+-K+ ATPase and the Cl- channel subunit barttin, and its absence increases the accessibility of the basolateral extracellular space to certain substances. Electron microscopy reveals a widening of basolateral membrane infoldings in the absence of Claudin-10b. These findings suggest that Claudin-10b may shape neighboring membrane invaginations through trans interaction, thereby stabilizing and facilitating high-flux salt transport.
ANNALS OF THE NEW YORK ACADEMY OF SCIENCES
(2022)
Article
Multidisciplinary Sciences
Hannes Gonschior, Christopher Schmied, Rozemarijn Eva Van der Veen, Jenny Eichhorst, Nina Himmerkus, Joerg Piontek, Dorothee Guenzel, Markus Bleich, Mikio Furuse, Volker Haucke, Martin Lehmann
Summary: Through super-resolution microscopy and fluorescence resonance energy transfer, this study reveals the nanoscale organization principles of tight junctions formed by different claudins. The segregation of channel-forming and barrier-forming claudins allows tight junctions to maintain their barrier function while enabling specific paracellular ion flux.
NATURE COMMUNICATIONS
(2022)
Article
Physiology
Natalia Kriuchkova, Tilman Breiderhoff, Dominik Mueller, Duygu Elif Yilmaz, Hasan Demirci, Hoora Drewell, Dorothee Guenzel, Nina Himmerkus, Markus Bleich, Pontus B. Persson, Kerim Mutig
Summary: Perturbed calcium homeostasis in familial hypomagnesaemia with hypercalciuria and nephrocalcinosis (FHHNC) limits life expectancy. FHHNC is caused by loss-of-function mutations in CLDN16 or CLDN19 genes, leading to impaired paracellular reabsorption of divalent cations in the cortical thick ascending limb (cTAL). Furosemide, a loop diuretic, can compensate for this impairment by activating Ca2+ transport proteins in the distal nephron and collecting duct, resulting in reduced hypercalciuria.
Article
Physiology
Dorothee Guenzel
Summary: The concept of solvent drag involves the frictional coupling between water and solutes in the same pore for transport. It has been applied to transport processes across cell membranes and along the paracellular pathway. Water-driven solute transport has been proposed as the major mechanism for absorption in the small intestine and reabsorption in the renal proximal tubule. However, the discovery of aquaporins and the claudin protein family has led to a reassessment of the solvent drag concept for transepithelial water and solute transport.
PFLUGERS ARCHIV-EUROPEAN JOURNAL OF PHYSIOLOGY
(2023)
Article
Multidisciplinary Sciences
Henrik Dimke, Camille Griveau, Wung-Man Evelyne Ling, Gaelle Brideau, Lydie Cheval, Pravina Muthan, Dominik Mueller, Amr Al-Shebel, Pascal Houillier, Caroline Prot-Bertoye
Summary: The kidney plays a critical role in maintaining mineral balance in the body. Dysregulation of calcium and magnesium reabsorption in the renal tubules can lead to familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC), which is characterized by excessive wasting of calcium and magnesium. This study investigated the localization of claudin-19 (CLDN19), a protein involved in mineral reabsorption, in the kidneys and found that it is primarily located in the basolateral membrane of the renal tubules. Additionally, the study showed that CLDN19 interacts with claudin-16 (CLDN16) to regulate permeability in the tubules. These findings provide insights into the pathophysiology of FHHNC and highlight the importance of CLDN19 in maintaining mineral homeostasis in the kidney.
ANNALS OF THE NEW YORK ACADEMY OF SCIENCES
(2023)
Review
Urology & Nephrology
Luca Meoli, Dorothee Guenzel
Summary: Sequential expression of claudins in the nephron mirrors the sequential expression of ion channels and transporters, contributing to the maintenance of electrolyte and water homeostasis. The regulation and dysregulation of claudins have been extensively studied in the gastrointestinal tract, but their role in the kidney is only just emerging. Investigating the role of claudins in kidney diseases may provide insights into potential prognostic markers or druggable targets.
NATURE REVIEWS NEPHROLOGY
(2023)
Article
Multidisciplinary Sciences
Matthias Wuttke, Eva Koenig, Maria-Alexandra Katsara, Holger Kirsten, Saeed Khomeijani Farahani, Alexander Teumer, Yong Li, Martin Lang, Burulca Goecmen, Cristian Pattaro, Dorothee Guenzel, Anna Koettgen, Christian Fuchsberger
Summary: A genotype imputation approach was applied to whole exome sequencing data from the UK Biobank, resulting in the discovery of 158 rare variants and 105 genes significantly associated with kidney function traits. This approach boosts statistical power and provides a comprehensive resource for directing experimental and clinical studies of kidney disease.
NATURE COMMUNICATIONS
(2023)
Article
Urology & Nephrology
Tobias Sieckmann, Gunnar Schley, Neslihan Oegel, Simon Kelterborn, Felix J. Boivin, Michael Faehling, Muhammad I. Ashraf, Martin Reichel, Emilia Vigolo, Andrea Hartner, Falk-Bach Lichtenberger, Tilman Breiderhoff, Felix Knauf, Christian Rosenberger, Felix Aigner, Kai Schmidt-Ott, Holger Scholz, Karin M. Kirschner
Summary: Experimental models have shown that impaired polyamine homeostasis contributes to various kidney pathologies, including ischemia-reperfusion, transplantation, rhabdomyolysis, cyclosporine treatment, arterial hypertension, diabetes, unilateral ureteral obstruction, high oxalate feeding, and adenine-induced injuries. These injuries lead to reduced expression of polyamine synthesis enzymes and increased expression of polyamine degrading enzymes, resulting in an imbalance of kidney polyamines.
KIDNEY INTERNATIONAL
(2023)
Article
Genetics & Heredity
Juilee Rege, Sascha Bandulik, Kazutaka Nanba, Carla Kosmann, Amy R. Blinder, Allein Plain, Pankaj Vats, Chandan Kumar-Sinha, Antonio M. Lerario, Tobias Else, Yuto Yamazaki, Fumitoshi Satoh, Hironobu Sasano, Thomas J. Giordano, Tracy Ann Williams, Martin Reincke, Adina F. Turcu, Aaron M. Udager, Richard Warth, William E. Rainey
Summary: This study identified mutations in the SLC30A1 gene associated with PA. The mutations are located near the zinc-binding site in the coding region of SLC30A1 and may cause abnormal ion transport. PA cases with SLC30A1 mutations showed male dominance and increased levels of aldosterone and 18-oxocortisol.