Silencing TRPC6 Gene Attenuates Hypertension‐induced Renal Injury in 5/6 Ablation/Infarction Model

Abstract

The transient receptor potential canonical 6 (TRPC6) channel is a member of the TRPC family. A “gain of function” mutation of TRPC6 causes familial focal segmental glomerulosclerosis (FSGS) and that overexpression of TRPC6 in podocytes causes a kidney disease consistent with FSGS in animals. Moreover, TRPC6 participates in the mechanical or pressure sensation in various cell types, including in the podocyte slit diaphragm. Therefore, TRPC6 may be the upstream mediator that transmits the pressure stress into downstream molecular pathways to cause hypertension‐induced renal injury. The present study tested the hypothesis that up‐regulated TRPC6 in the kidney mediates the hypertension‐induced renal injury in rats with 5/6 renal ablation/infarction (A/I), a model in which the renal injury is closely associated with blood pressure. Adults male Sprague Dawley rats were divided into shame group, 5/6 A/I control group and 5/6 A/I shRNA group. The left kidneys of shame and 5/6 A/I control groups were treated with intra‐renal transfection of control plasmids and the 5/6 A/I shRNA group TRPC6 shRNA plasmids. The results showed that the levels of renal TRPC6 was increased in 5/6 A/I control group compared with shame group and that the increase of TRPC6 was blocked in 5/6 A/I shRNA groups, the relative protein levels of TRPC6 were 1.0±0.26, 3.9±0.16 and 1.4±0.17 in shame, 5/6 A/I control and 5/6 A/I shRNA groups, respectively. TRPC6 shRNA had no effect on hypertension in 5/6 A/I rats (MAP: 153.9 ± 8.1 mmHg in control groups vs. 154.7 ± 8.9 mmHg in shRNA groups). However, the albuminuria was attenuated in 5/6 A/I shRNA group compared with 5/6 A/I control group. The levels of urinary albumin were 0.8±0.34 mg/Kg/24h in shame, 20.82± 3.7 mg/Kg/24h in 5/6 A/I control and 11.9±1.5 mg/Kg/24h in 5/6 A/I shRNA group, respectively (P=0.037 for control vs. shRNA groups). The regression slop between the blood pressure and the % of glomerulosclerosis was significantly steeper in 5/6 A/I control group than in 5/6 A/I shRNA group (P=0.028 by ANCOVA), indicating a significant attenuation of hypertension‐induced glomerular injuries. These data suggested that hypertension‐induced activation of TRPC6 may be the molecular sensor of pressure stress to produce kidney damage associated with hypertension. (Supported by NIH grants DK107991 to NL and DK54927 to PL).Support or Funding InformationNIH grants DK107991 to NL and DK54927 to PLThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.