Nephron-specific knockout of TMEM16A leads to reduced number of glomeruli and albuminuria

Schenk, Laura K.; Buchholz, Björn; Henke, Sebastian Franz; Michgehl, Ulf; Daniel, Christoph; Amann, Kerstin; Kunzelmann, Karl; Pavenstädt, Hermann

doi:10.1152/ajprenal.00638.2017

Cited by 15 publications

(10 citation statements)

References 31 publications

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“…In contrast to He et al, we found that ongoing activation of ANO1 (or ANO6) by either ionomycin or purinergic stimulation increased intracellular Cl − concentrations in HEK293 and HeLa cells [102]. Nevertheless the proposed concept that intracellular Cl − levels determine vesicular endocytosis/exocytosis, control apical membrane delivery and morphogenesis [175], is interesting and corresponds well to the role of ANO1 in exocytosis and normal renal development detected in recent studies [107,175,176,177] (Figure 5). It is also noteworthy that intracellular Cl − regulation by ANO1 has been shown to participate in transcription of human epidermal growth factor receptor 2, which mediates PI3K/AKT/mTOR and JAK/STAT3 signaling pathways [52].…”

Section: The Role Of Anoctamins In Controlling Intracellular Cl− Csupporting

confidence: 72%

Contribution of Anoctamins to Cell Survival and Cell Death

Kunzelmann

Ousingsawat

Benedetto

et al. 2019

Cancers

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Before anoctamins (TMEM16 proteins) were identified as a family of Ca2+-activated chloride channels and phospholipid scramblases, the founding member anoctamin 1 (ANO1, TMEM16A) was known as DOG1, a marker protein for gastrointestinal stromal tumors (GIST). Meanwhile, ANO1 has been examined in more detail, and the role of ANO1 in cell proliferation and the development of different types of malignomas is now well established. While ANO5, ANO7, and ANO9 may also be relevant for growth of cancers, evidence has been provided for a role of ANO6 (TMEM16F) in regulated cell death. The cellular mechanisms by which anoctamins control cell proliferation and cell death, respectively, are just emerging; however, the pronounced effects of anoctamins on intracellular Ca2+ levels are likely to play a significant role. Recent results suggest that some anoctamins control membrane exocytosis by setting Ca2+i levels near the plasma membrane, and/or by controlling the intracellular Cl− concentration. Exocytosis and increased membrane trafficking induced by ANO1 and ANO6 may enhance membrane expression of other chloride channels, such as CFTR and volume activated chloride channels (VRAC). Notably, ANO6-induced phospholipid scrambling with exposure of phosphatidylserine is pivotal for the sheddase function of disintegrin and metalloproteinase (ADAM). This may support cell death and tumorigenic activity of IL-6 by inducing IL-6 trans-signaling. The reported anticancer effects of the anthelminthic drug niclosamide are probably related to the potent inhibitory effect on ANO1, apart from inducing cell cycle arrest through the Let-7d/CDC34 axis. On the contrary, pronounced activation of ANO6 due to a large increase in intracellular calcium, activation of phospholipase A2 or lipid peroxidation, can lead to ferroptotic death of cancer cells. It therefore appears reasonable to search for both inhibitors and potent activators of TMEM16 in order to interfere with cancer growth and metastasis.

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Section: The Role Of Anoctamins In Controlling Intracellular Cl− Csupporting

confidence: 72%

Contribution of Anoctamins to Cell Survival and Cell Death

Kunzelmann

Ousingsawat

Benedetto

et al. 2019

Cancers

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“…18,21 ). Along this line, it was shown that knockdown of TMEM16A during kidney development affects ciliogenesis and reduces the number of renal glomeruli, thus causing albuminuria 41,42 .…”

Section: Discussionmentioning

confidence: 97%

Cyst growth in ADPKD is prevented by pharmacological and genetic inhibition of TMEM16A in vivo

et al. 2020

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In autosomal dominant polycystic kidney disease (ADPKD) multiple bilateral renal cysts gradually enlarge, leading to a decline in renal function. Transepithelial chloride secretion through cystic fibrosis transmembrane conductance regulator (CFTR) and TMEM16A (anoctamin 1) are known to drive cyst enlargement. Here we demonstrate that loss of Pkd1 increased expression of TMEM16A and CFTR and Cl − secretion in murine kidneys, with TMEM16A essentially contributing to cyst growth. Upregulated TMEM16A enhanced intracellular Ca 2+ signaling and proliferation of Pkd1-deficient renal epithelial cells. In contrast, increase in Ca 2+ signaling, cell proliferation and CFTR expression was not observed in Pkd1/Tmem16a double knockout mice. Knockout of Tmem16a or inhibition of TMEM16A in vivo by the FDA-approved drugs niclosamide and benzbromarone, as well as the TMEM16A-specific inhibitor Ani9 largely reduced cyst enlargement and abnormal cyst cell proliferation. The present data establish a therapeutic concept for the treatment of ADPKD.

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“…Inhibition of TMEM16A may also attenuate intestinal contraction and abdominal peristalsis (Sanders et al, 2012; Singh et al, 2014), and therefore could have antidiarrheal effects (Tradtrantip et al, 2010; Namkung et al, 2011b; Jiang et al, 2016). Finally, inhibition of renal TMEM16A could potentially lead to proteinuria and acidosis (Faria et al, 2014; Schenk et al, 2018). For activators of TMEM16A, opposite effects are possible, which is why local application via aerosol may be recommended for the treatment of CF lung disease.…”

Section: Biological Effects Of Inhibitors and Activators Of Tmem16amentioning

confidence: 99%

TMEM16A in Cystic Fibrosis: Activating or Inhibiting?

et al. 2019

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The inflammatory airway disease cystic fibrosis (CF) is characterized by airway obstruction due to mucus hypersecretion, airway plugging, and bronchoconstriction. The cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel is dysfunctional in CF, leading to defects in epithelial transport. Although CF pathogenesis is still disputed, activation of alternative Cl− channels is assumed to improve lung function in CF. Two suitable non-CFTR Cl− channels are present in the airway epithelium, the Ca2+ activated channel TMEM16A and SLC26A9. Activation of these channels is thought to be feasible to improve hydration of the airway mucus and to increase mucociliary clearance. Interestingly, both channels are upregulated during inflammatory lung disease. They are assumed to support fluid secretion, necessary to hydrate excess mucus and to maintain mucus clearance. During inflammation, however, TMEM16A is upregulated particularly in mucus producing cells, with only little expression in ciliated cells. Recently it was shown that knockout of TMEM16A in ciliated cells strongly compromises Cl− conductance and attenuated mucus secretion, but does not lead to a CF-like lung disease and airway plugging. Along this line, activation of TMEM16A by denufosol, a stable purinergic ligand, failed to demonstrate any benefit to CF patients in earlier studies. It rather induced adverse effects such as cough. A number of studies suggest that TMEM16A is essential for mucus secretion and possibly also for mucus production. Evidence is now provided for a crucial role of TMEM16A in fusion of mucus-filled granules with the apical plasma membrane and cellular exocytosis. This is probably due to local Ca2+ signals facilitated by TMEM16A. Taken together, TMEM16A supports fluid secretion by ciliated airway epithelial cells, but also maintains excessive mucus secretion during inflammatory airway disease. Because TMEM16A also supports airway smooth muscle contraction, inhibition rather than activation of TMEM16A might be the appropriate treatment for CF lung disease, asthma and COPD. As a number of FDA-approved and well-tolerated drugs have been shown to inhibit TMEM16A, evaluation in clinical trials appears timely.

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Nephron-specific knockout of TMEM16A leads to reduced number of glomeruli and albuminuria

Cited by 15 publications

References 31 publications

Contribution of Anoctamins to Cell Survival and Cell Death

Contribution of Anoctamins to Cell Survival and Cell Death

Cyst growth in ADPKD is prevented by pharmacological and genetic inhibition of TMEM16A in vivo

TMEM16A in Cystic Fibrosis: Activating or Inhibiting?

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