Abstract
The mechanisms underlying vascular complications in autosomal-dominant polycystic kidney disease (ADPKD) have not been fully elucidated. However, molecular components altered in Pkd mutant vascular smooth muscle cells (VSMCs) are gradually being identified. Pkd2+/-arterial smooth muscles show elevated levels of (1) phenylephrine (PE)-induced, Ca2+independent vasocontraction and (2) smooth muscle α-actin (SMA) expression. As these two processes are heavily influenced by RhoA signaling and by cellular filamentous-to-globular (F/G)-actin dynamics, we examined PE-induced changes in RhoA activation and the F/G-SMA ratio in wild-type (wt) and Pkd2 +/-VSMCs; we further tested the hypothesis that the abnormal response to PE and the resultant elevation in the F/G-SMA ratio contribute to the exuberant SMA expression in Pkd2+/-VSMCs. GTP-RhoA and F/G-SMA in mouse aortic media and primary cultured VSMCs were determined using RhoA activation and in vivo F-to-G-actin assays. Myocardin-related transcription factor-A (MRTF-A) (SMA transcription coactivator) was localized by immunofluorescence, nuclear MRTF-A quantified by western analysis using nuclear extracts and SMA expression by luciferase reporter assay. PE induced a 3-fold higher RhoA activation in Pkd2+/-than in wt VSMCs and higher levels of downstream p-LIMK and p-cofilin. Moreover, Pkd2+/-VSMCs showed a higher baseline and PE-induced F/G-SMA ratio. The F/G-SMA elevation enhanced nuclear translocation of MRTF-A, which upregulated SMA transcription. In summary, PE-induced RhoA hyperactivation and defects in F-to-G SMA balance likely have a role in the abnormal vasocontraction and SMA expression in Pkd2+/- arteries. These defects could potentially contribute to the genesis of vascular complications in ADPKD, thus providing new areas for further research and therapeutic targeting.
Original language | English (US) |
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Pages (from-to) | 37-42 |
Number of pages | 6 |
Journal | Hypertension Research |
Volume | 33 |
Issue number | 1 |
DOIs | |
State | Published - Jan 2010 |
Keywords
- MRTF
- Polycystin
- RhoA
- SM alpha;-actin
- Vascular smooth muscle cells
ASJC Scopus subject areas
- Internal Medicine
- Physiology
- Cardiology and Cardiovascular Medicine