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How the renin-angiotensin system leads to visual impairments

by Chen Xufeng (03.09.2012)

The eye is one of the most important sensory organs in humans. However, more than one million people in Germany suffer from visual handicaps. A relatively common group of eye diseases are macula degenerations, among which the age-related macular degeneration (AMD) represents the most common cause of retinal degeneration in elderly people. AMD is caused by a loss of cells of the retinal pigment epithelium (RPE). RPE cells are adjacent to the neurosensory retina that nourishes photoreceptors (Fig. 1). During my work at the Experimental and Clinical Neurosciences (ECN) programme at the University of Regensburg, I examined the role of the renin-angiotensin system (RAS) on regulating membrane potentials of RPE cells. My research revealed that it plays a crucial role as a risk factor in AMD.

Fig. 1: Eye structure and retina section.[Bildunterschrift / Subline]: Fig. 1: Eye structure and retina section.

All metabolites of the RAS origin from angiotensinogen. Angiotensinogen is cleaved by renin to form Angiotension I. Angiotension I is then converted to angiotension II (AngII) by another protease called angiotensin-converting enzyme (ACE). It was found that AngII receptors (ATR) and the angiotensin receptor associated protein (Atrap) are expressed on the blood side of RPE cells. Moreover, the research group of Prof. Olaf Strauß at the University of Regensburg recently found that AngII causes an increase of intracellular free Ca2+ in RPE cells (Milenkovic et al. 2010, AJP) (Fig. 2). The increase of intracellular free Ca2+ stimulated renin expression in the RPE. This renin is then secreted to the retina where it modulates the local RAS.

Fig. 2: Systemic AngII binds ATR (AngiotensinII receptor) on RPE cells leading to an increase of intracellular calcium (Ca<sup>2+</sup>) via calcium-dependent membrane channels. This study examined which Ca2+-channels are involved.[Bildunterschrift / Subline]: Fig. 2: Systemic AngII binds ATR (AngiotensinII receptor) on RPE cells leading to an increase of intracellular calcium (Ca2+) via calcium-dependent membrane channels. This study examined which (Ca2+)-channels are involved.

We hypothesized that the sustained increase of Ca2+ in the presence of AngII results from transient receptor potential channels. Therefore, I measured the membrane currents by a perforated-patch recording technique (Fig. 3) from a primary culture of pig RPE cells under extra- and intracellular K+-free conditions at a holding potential of -40 mV. In order to distinguish between Ca2+ and K+ currents, cells activated by AngII were repeatedly stimulated by voltage ramps from -140 mV to +60 mV. Additionally, I tested the current flow in the presence of SKF96365, a T-type Ca2+ channel blocker. My results showed that AngII led to an inward current, which was accompanied by a shift of the reversal potential of the membrane currents indicating the activation of a non-specific cation current. Cells treated with a Ca2+ channel blocker (SKF96365) did neither show inward current activation nor shifts in the reversal potential. We further hypothesized that the TRPV2 channel, a special type of Ca2+ channel, is involved in the generation of the currents. Therefore, I investigated cells in which the TRPV2 expression was down-regulated by RNAi (RNA interference) against TRPV2 channel. Although the RNAi treated cells still showed an inward current during AngII stimulation, this current was insensitive to SKF96365.As a control, I examined cells with scrambled or not TRPV2-specific siRNA (small interference RNA). Here, the cell AngII-activated currents were also sensitive to the Ca2+ channel blocker.

Fig. 3: The perforated-patch recording technique.[Bildunterschrift / Subline]: Fig. 3: The perforated-patch recording technique.

In summary, my results showed that angiotension II (AngII) substantially activates calcium-conducting ion channels. Among the tested ion channels only the TRPV2 channel was affected. These results illuminate our understanding in how changes in the renin-angiotensin system promote local events that lead to substantial visual impairments.

Further Information

Chen Xufeng
* 1985

  • current
  • Master's thesis in Experimental Ophthalmology, Eye Hospital, University Medical Center Regensburg
  • 10/2010 until now
  • Master programme in Experimental and Clinical Neurosciences (ECN), University of Regensburg
  • 09/2005 - 06/2009
  • Bachelor programme in Biotechnology, Hainan University, China