Renal epithelial ion channels

Renal epithelial ion channels
Renal epithelial ion channels
Korbmacher, Christoph

A main research focus of the group of Prof. Korbmacher is the epithelial sodium channel (ENaC) which is a member of the ENaC/degenerin family of ion channels. ENaC is localized in the apical membrane of epithelial cells and is the rate limiting step for sodium absorption in epithelial tissues including the aldosterone-sensitive distal nephron (ASDN). Abnormal ENaC activation in the ASDN may cause sodium retention and arterial hypertension. ENaC is one of the key targets of aldosterone. However, the molecular mechanisms involved in ENaC regulation in the ASDN are highly complex [1] and include aldosterone-dependent and independent mechanisms [2]. For example ENaC activity can be stimulated by norepinephrine [3] which may contribute to the hypertensive effect of increased renal sympathetic activity. A unique feature of ENaC is its proteolytic activation which involves specific cleavage sites and the release of inhibitory peptide fragments. The physiologically relevant proteases involved in ENaC regulation remain to be identified [4, 5]. Moreover, it has to be determined how these proteases are regulated and linked to ENaC regulation by aldosterone. A better understanding of the mechanisms involved in ENaC regulation will hopefully provide novel insights into the physiology and pathophysiology of arterial hypertension. This ultimately may lead to new diagnostic and therapeutic concepts.

An emerging additional research focus of our group is the physiology and pathophysiology of the TRPV4 ion channel in the context of polycystic kidney disease. This ion channel is highly expressed in the distal tubule where renals cyst formation occurs. So far littel is known about the role of TRPV4 in tubular function and transport. Interestingyl, TRPV4 appears to be regulated by the protease-activated recptor 2 (PAR2) which may be relavant in the context of inflammatory disease with locally released proteases [6].

1. Loffing J, Korbmacher C (2009) Regulated sodium transport in the renal connecting tubule (CNT) via the epithelial sodium channel (ENaC). Pflugers Arch 458:111-35 (PMID: 19277701)

2. Nesterov V, Dahlmann A, Krueger B, Bertog M, Loffing J, Korbmacher C (2012) Aldosterone-dependent and -independent regulation of the epithelial sodium channel (ENaC) in mouse distal nephron. Am J Physiol Renal Physiol 303: F1289-99 (PMID: 22933298)

3. Mansley MK, Neuhuber W, Korbmacher C, Bertog M (2015) Norepinephrine stimulates the epithelial Na+ channel in cortical collecting duct cells via α2-adrenoceptors. Am J Physiol Renal Physiol 308: F450-8 (PMID: 25520009)

4. Haerteis S, Krappitz M, Diakov A, Krappitz A, Rauh R, Korbmacher C. 2012. Plasmin and chymotrypsin have distinct preferences for channel activating cleavage sites in the γ subunit of the human epithelial sodium channel. J Gen Physiol 140: 375-89 (PMID: 22966015)

5. Haerteis S, Krappitz A, Krappitz M, Murphy JE, Bertog M, Krueger B, Nacken R, Chung H, Hollenberg MD, Knecht W, Bunnett NW, Korbmacher C (2014) Proteolytic activation of the human epithelial sodium channel by trypsin IV and trypsin I involves distinct cleavage sites. J Biol Chem 289: 19067-78 (PMID: 24841206)

6. Sostegni S, Diakov A, McIntyre P, Bunnett N, Korbmacher C, Haerteis S (2015) Sensitisation of TRPV4 by PAR2 is independent of intracellular calcium signalling and can be mediated by the biased agonist neutrophil elastase. Pflugers Arch. 467:687-701 (PMID: 24906497)

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Renal epithelial ion channels