Clemizole and La 3+ salts ameliorate angiotensin II-induced glomerular hyperpermeability in vivo

Angiotensin II (Ang II) induces marked, dynamic increases in the permeability of the glomerular filtration barrier (GFB) in rats. After binding to its receptor, Ang II elicits Ca influx into cells, mediated by TRPC5 and TRPC6 (transient receptor potential canonical type 5 and 6). Clemizole and La salts have been shown to block TRPC channels in vitro, and we therefore tested their potential effect on Ang II-induced glomerular hyperpermeability. Anesthetized male Sprague-Dawley rats were infused with Ang II (80 ng kg min ) alone, or together with clemizole or low-dose La (activates TRPC5, blocks TRPC6) or high-dose La (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 for Ficoll 10-80 Å (1-8 nm). Ang II infusion evoked glomerular hyperpermeability to large Ficolls (50-80 Å), which was ameliorated by clemizole, having no significant effect on glomerular filtration rate (GFR) or Ang II-mediated increase in mean arterial pressure (ΔMAP). In contrast, high- and low-dose La significantly lowered ΔMAP and reduced Ang II-induced hyperpermeability. Combined, clemizole and low-dose La were less effective at ameliorating Ang II-induced glomerular hyperpermeability than low-dose La alone. In conclusion, our data show that both clemizole and La3+ are effective against Ang II-induced glomerular hyperpermeability, with differential effects on blood pressure. Further research using more specific blockers of TRPC5 and TRPC6 should be performed to reveal the underlying mechanisms.