Regulation and Function of TMEM16F in Renal Podocytes

Int J Mol Sci. 2018 Jun 18;19(6):1798. doi: 10.3390/ijms19061798.

Abstract

The Ca2+-activated phospholipid scramblase and ion channel TMEM16F is expressed in podocytes of renal glomeruli. Podocytes are specialized cells that form interdigitating foot processes as an essential component of the glomerular filter. These cells, which participate in generation of the primary urine, are often affected during primary glomerular diseases, such as glomerulonephritis and secondary hypertensive or diabetic nephropathy, which always leads to proteinuria. Because the function of podocytes is known to be controlled by intracellular Ca2+ signaling, it is important to know about the role of Ca2+-activated TMEM16F in these cells. To that end, we generated an inducible TMEM16F knockdown in the podocyte cell line AB8, and produced a conditional mouse model with knockout of TMEM16F in podocytes and renal epithelial cells of the nephron. We found that knockdown of TMEM16F did not produce proteinuria or any obvious phenotypic changes. Knockdown of TMEM16F affected cell death of tubular epithelial cells but not of glomerular podocytes when analyzed in TUNEL assays. Surprisingly, and in contrast to other cell types, TMEM16F did not control intracellular Ca2+ signaling and was not responsible for Ca2+-activated whole cell currents in podocytes. TMEM16F levels in podocytes were enhanced after inhibition of the endolysosomal pathway and after treatment with angiotensin II. Renal knockout of TMEM16F did not compromise renal morphology and serum electrolytes. Taken together, in contrast to other cell types, such as platelets, bone cells, and immune cells, TMEM16F shows little effect on basal properties of podocytes and does not appear to be essential for renal function.

Keywords: TMEM16F; anoctamin 6; chloride channel; kidney; renal ion channels.

MeSH terms

  • Action Potentials
  • Animals
  • Anoctamins / genetics*
  • Anoctamins / metabolism
  • Apoptosis
  • Calcium Signaling
  • HEK293 Cells
  • Humans
  • Mice
  • Phenotype
  • Phospholipid Transfer Proteins / genetics*
  • Phospholipid Transfer Proteins / metabolism
  • Podocytes / metabolism*
  • Podocytes / physiology

Substances

  • ANO6 protein, mouse
  • Anoctamins
  • Phospholipid Transfer Proteins