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Research:

 

The pivotal function of the kidney is to excrete solutes and some small molecules found in the blood and then selectively reabsorb those that need to be conserved while allowing others to be excreted in the urine. The permeability of renal tubules to different solutes and water is determined by the epithelial cells lining these structures. Renal re-absorption is a synchronized interplay between an array of epithelial ion channels and transporters at the expense of energy molecules (Transcellular). Kidney also utilizes the organelles at the cell-cell junctions to transport ions (Paracellular). Impairment in these two trans-epithelial ion transport mechanisms lead to a wide range of kidney disorders characterized by low potassium levels (hypokalemia), increased blood pH (alkalosis), low magnesium levels (Hypomagnesemia), excess amounts of calcium in the urine (hypercalciuria) and kidneys (nephrocalcinosis) eventually leading to kidney stones and renal failure.

 

Inherited Salt wasting Tubulopathies:

 

Approximately 25% of the filtered NaCl is reabsorbed by the thick ascending limb (TAL) of Henle’s loop by a well coordinated action of transportation proteins (Figure 1A). Identification of transportation processes involving these proteins facilitated the elucidation of rare, recessively inherited tubulopathies including Bartter’s (BS) and Gitelman’s (GS) syndrome, associated with massive to mild salt wasting and lethality respectively. Despite these advancements in clinical genetics more than 40% of our patients (n=500) with innate salt wasting disorders are genetically inexplicable (Figure 1B). Therefore, it is tempting to speculate whether the already known transport systems in the TAL epithelia are described to their actual completeness? In a quest to identify novel genes associated with renal salt handling, we performed a membrane yeast two hybrid (mY2H) screening using the renal outer medullary potassium channel (ROMK2), as a bait.

Figure1
Figure1

 

Figure1: A. Mechanism of transepithelial salt transport in the Thick ascending limb of Henle’s Loop (TAL) and associated kidney disorders (BSND- Bartter’s Syndrome, FHHNC- familial hypercalciuric hypomagnesemia with nephrocalcinosis, HN- Hypercalciuric Nephrolithiasis). The apical potassium channel ROMK serves the potassium secretion in the TAL and has long been speculated to associate with a yet to be identified accessory subunit. The basolateral chloride channels CLC-Ka and –Kb associate with the accessory subunit Barttin. Continuous transcellular NaCl reabsorption along TAL results in a lumen-positive transepithelial diffusion potential. This positive potential drives the paracellular reabsorption of Mg2+ and Ca2+ through the TJ. Cation selectivity of tight junctions is owing to interacting claudins (CLDN). B. Distribution of Genotypes in our patients with congenital salt wasting tubulopathies (n=504). Despite considerable advances in genetic diagnostics, almost 40% of the cases remain unexplained. Included in the statistics are the patients with Gitelman-syndrome (resulting from the genetic defect of NaCl transporter NCCT)

 

Why ROMK2?

ROMK2 is a key player in the process of salt reabsorption along the TAL and makes a promising candidate for mY2H screening, as the existence of a modulating beta subunit to this channel has been previously postulated owing to two reasons. Firstly, many experimental evidences reported the presence of two different potassium conductances in the luminal cell membrane of the TAL. The ROMK channel appears to be responsible for both the conductances, as animal models with genetic ablation of ROMK showed neither of the two conductivities (Lu. M., et al). Secondly, Other potassium channels of the same family are associated with obligatory subunits. For example, the KATP channels in the insulin-producing B-cells of the pancreas are heterotetramers containing Kir6,2 and an ABC protein- SUR2A (Inagaki. N., et al).

Screening a Kidney cDNA library, we identified a number of interesting proteins that interact with ROMK2. The functional characterization of these interactions and further genetic screening of the above mentioned patients for mutations in promising interactomes (eg: THGP, SLCs and ABC protein) is the major focus of our research.

 

Co-operation projects:

 

EAST / SeSAME Syndrome:

 

The spectrum of renal salt wasting is continuously evolving by newly described syndromes (EAST/SeSAME) in which defective tubular ion transport coincides with other symptoms ranging from mental retardation, ataxia, epilepsy to sensorineural deafness. The tubulopathy in these patients shares many biochemical abnormalities with patients affected with BS/GS, namely renal salt loss, hypokalemic alkalosis and hypomagnesemia. This new disorder is caused by mutations in the inwardly-rectifying K+ channel Kir4.1. Till date, many studies have reported mutations in Kir4.1 leading to EAST/SeSAME syndrome. In a separate genetic screening (for Kir4.1 and Kir5.1) performed at the University Hospital Muenster (A.G: Prof. Dr. Martin Konrad) involving 74 patients with classic BS/GS like phenotype but lacking mutations in any of the known classical genes, 3 missense mutations and a single base pair deletion in Kir4.1 and a novel missense mutation in Kir5.1 was identified. Functional characterization of these mutations highlighted the role of Kir5.1/Kir4.1 heteromers in renal salt handling, thereby warranting the importance of identification of other proteins, ligands or auxillary subunits that regulates the function of these Kir subunits. 

 

Inherited renal calcification Tubulopathies (FHHNC and HN):

 

In co-operation with the university of Washington (A.G: Prof. Jianghui Hou) we are studying the role of claudins (CLDN) in renal salt handling. Our studies contributed towards the understanding of the genetic causes of the pathogenesis of Familial Hypercalciuric Hypomagnesemia with Nephrocalcinosis (FHHNC) with ocular impairment and elucidated the role of CLDNs –16 and –19 heteromers as cation channels for the permeation of divalent cations like Ca+2 and Mg+2. More recently we identified that CLDN –14 forms higher oligomeric complexes with –16 and –19  and abolishes their cation selectivity, thereby increasing calcium accumulation leading to Hypercalciuric Nephrolithiasis (HN). 

 

Selected Publications:

 

1.      Renigunta A, Renigunta V, Saritas T, Decher N, Mutig K, Waldegger S. (2011). Tamm-Horsfall Glycoprotein interacts with renal potassium channel ROMK2 and regulates its function. J Biol Chem. 286(3):2224-35

 

2.      Renigunta A, Mutig K, Rottermann K, Schlichthörl G, Preisig-Müller R, Daut J, Waldegger S, Renigunta V. (2011). The glycolytic enzymes glyceraldehyde 3-phosphate dehydrogenase and enolase interact with the renal epithelialK+ channel ROMK2 and regulate its function. Cell Physiol Biochem. 28(4):663-72

3.      Hou J, Renigunta A, Konrad M, Gomes AS, Schneeberger EE, Paul DL, Waldegger S, Goodenough DA. (2008). Claudin-16 and Claudin-19 interact and form a cation selective tight junction complex. J Clin Invest. 118(2):619-28.

 

4.      Hou J, Renigunta A, Gomes AS, Hou M, Paul DL, Waldegger S, Goodenough DA. (2009). Claudin-16 and claudin-19 interaction is required for their assembly into tight junctions and for renal reabsorption of magnesium. Proc Natl Acad Sci U S A. 106(36):15350-5.

 

5.      Hou J, Renigunta A, Yang J, Waldegger S. (2010) Claudin-4 forms paracellular chloride channel in the kidney and requires claudin-8 for tight junction localization. Proc Natl Acad Sci U S A. 107(42):18010-5.

6.      Gong Y, Renigunta V, Himmerkus N, Zhang J, Renigunta A, Bleich M, Hou J. (2012). Claudin-14 regulates renal Ca++ transport in response to CaSR signaling via a novel microRNA pathway. EMBO J. 31(8):1999-2012

 

 

 

Open Positions:

Medical students interested in MD studies (Doktor arbeit) may contact the principle investigator for further details.


 

Contact:

 

Director

Prof. Dr. Rolf. F. Maier

Tel:+49 642158 62650

rolf.maier@med.uni-marburg.de

 

Principle Investigator

 

Dr. Aparna Renigunta

Tel: +49 642158 62968

aparna.renigunta@staff.uni-marburg.de

 

Technical Assistant

Christina Rösser

Tel: +49 642158 62478

 christina.roesser@med.uni-marburg.de

 

Alexandra Schneider

Tel: +49 642158 62789

wassmuth@med.uni-marburg.de

                     

Zuletzt aktualisiert: 28.05.2015 · sontowsk

 
 
 
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