Kidney Week

Abstract: SA-PO316

Differential Effects of TRPC5 and TRPC6 Channels in Angiotensin II Induced Glomerular Hyperpermeability

Session Information

• Cellular Crosstalk in Glomerular Diseases - II
  October 27, 2018 | Location: Exhibit Hall, San Diego Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: CKD (Non-Dialysis)

• 1903 CKD (Non-Dialysis): Mechanisms

Authors

• Öberg, Carl Mikael, Lund University, Lund, Sweden

Carl Mikael Öberg,

• Dolinina, Julia, Lund University, Lund, Sweden

Julia Dolinina,

• Rippe, Anna, Lund University, Lund, Sweden

Anna Rippe,

Group or Team Name

• Renal Physiology & Peritoneal Dialysis Group

Background

Angiotensin II (Ang II) rapidly induces marked, dynamic increases in the permeability of the glomerular filtration barrier (GFB) in rats. After binding to its receptor(s), Ang II elicits Ca²⁺ influx into cells mediated by TRPC5 and TRPC6 (transient receptor potential canonical type 5 and 6). We here identifed TRPC5 and TRPC6 as regulators of Ang II induced glomerular hyperpermeability while the latter also appears to be involved in the hemodynamic effects induced by Ang II.

Methods

In anesthetized Sprague-Dawley rats, the left ureter was cannulated for urine collection and blood access was achieved. Rats were infused with Ang II (80 ng kg^–1 min^–1) alone, or together with the TRPC5 blocker clemizole or low dose La³⁺ (activates TRPC5, blocks TRPC6) or high dose La³⁺ (blocks both TRPC5 and TRPC6). Plasma and urine samples were taken during baseline and at 5 min after the start of the infusions and analyzed by high-performance size-exclusion chromatography for determination of glomerular sieving coefficients (θ) for Ficoll 10-80Å (1-8 nm).

Results

Ang II infusion into rats caused marked increases in glomerular permeability to large Ficoll molecules (Ficoll 50–80Å), which were abrogated by the TRPC5 blocker clemizole, having no effect on glomerular filtration rate (GFR) or Ang II mediated increase in MAP (ΔMAP). In contrast, agents blocking TRPC6 (high and low dose La³⁺) significantly lowered ΔMAP and nearly completely abrogated Ang II induced hyperpermeability effects. The higher dose of La³⁺, blocking both TRPC5 and TRPC6, significantly lowered left-kidney GFR.

Conclusion

Our data unveil differential effects of Ca²⁺ signaling via TRPC5 and TRPC6 following Ang II stimulation. Especially, it appears that inhibition of TRPC5 in rats can abrogate AngII-induced glomerular hyperpermeability without affecting GFR or Ang II induced increases in MAP. Inhibition of TRPC5 may thus be a potential target for a novel antiproteinuric agent.

Funding

• Government Support - Non-U.S.