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. 2010 Mar;7(3):1126-38.
doi: 10.1111/j.1743-6109.2009.01634.x. Epub 2010 Jan 6.

Gene transfer of TRPC6 (dominant negative) restores erectile function in diabetic rats

Jae Hun Jung  1 , Byung Joo Kim, Mee Ree Chae, Sung Chul Kam, Ju-Hong Jeon, Insuk So, Ky Hyun Chung, Sung Won Lee
Affiliations

Gene transfer of TRPC6 (dominant negative) restores erectile function in diabetic rats

Jae Hun Jung et al. J Sex Med. 2010 Mar.

Abstract

Introduction: Transient receptor potential (TRP) channels play an important role in modulating intracellular Ca(2+) ([Ca(2+)](i)) levels.

Aim: We examined the hypothesis that overexpression of TRPC6(DN) (dominant negative) may contribute to decreased [Ca(2+)](i) levels in corporal smooth muscle (CSM). We also investigated whether gene transfer of TRPC6(DN) could restore erectile function in diabetic rats.

Methods: For the in vitro study, the K(Ca), K(ATP), and TRPC6(DN) channel genes were transferred using cDNA, into cultured human CSM cells and human embryonic kidney cells. For the in vivo study, young adult rats were divided into three groups: normal controls; diabetic controls transfected with vector only; and a diabetic group transfected with pcDNA of the TRPC6(DN) gene.

Main outcome measures: After gene transfer, the effects of reducing [Ca(2+)](i) levels were assessed by Fura-2-based imaging analysis. The intracavernosal pressure (ICP) response to cavernosal nerve stimulation was assessed after intracorporal injection of TRPC6(DN) pcDNA. The transgene expression of the TRPC6(DN) was examined by reverse transcription polymerase chain reaction (RT-PCR) in rats transfected with TRPC6(DN) pcDNA.

Results: Gene transfer of ion channels effectively reduced [Ca(2+)](i). Among these channels, transfer of the TRPC6(DN) gene resulted in the greatest reduction of [Ca(2+)](i) in human CSM. The mean (+/-standard error of the mean) ratio of ICP to mean arterial pressure (BP) in the gene-transfer rats was 79.4 +/- 2.4% (N = 8). This was significantly higher than that in control rats (55.6 +/- 3.7% [N = 8]), and similar to that in the young control rats (83 +/- 2.2% [N = 12]). The RT-PCR showed expression of TRPC6(DN) genes in the transfected rats.

Conclusion: Gene transfer of TRPC6(DN) not only reduced [Ca(2+)](i) in human CSM but also restored erectile function in diabetic rats. These results suggest that pcDNA transfer of TRPC6(DN) may represent a promising new form of therapy for the treatment of male erectile dysfunction in the future.

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