Down‐Regulation of Gamma‐Adducin Disrupts the Actin Cytoskeleton in FHH rats and May Contribute to the Development of Hypertension‐induced Renal Injury

Abstract

Fawn Hooded Hypertensive (FHH) rat develops chronic kidney disease after onset of hypertension. We previously reported that the expression of Add3 is decreased in various tissues, including kidney and renal vessels in FHH rats. More recently, we demonstrated that Add3 dysfunction contributes to renal vascular dysfunction in FHH rats, and they exhibit enhanced glomerular injury, interstitial fibrosis and proteinuria after the development of hypertension. Add3 is an actin‐binding protein that regulates actin capping and polymerization. The tail of the dimerized adducin protein interacts with actin and spectrin. However, it remains to be elucidated whether Add3 dysfunction alters actin cytoskeleton and contributes to renal microvascular dysfunction in FHH rats. The present study examined the role of Add3 on the regulation of the actin cytoskeleton in a vascular smooth muscle (VSMC) cell line treated with an Add3 DsiRNA, and in primary VSMCs isolated from FHH and FHH. Add3 transgenic rats. Downregulation of Add3 disrupted the actin cytoskeletal structural integrity in VSMC cells transfected with an Add3 DsiRNA (20 nM) in comparison to untreated or scramble siRNA treated cells. F‐actin distribution was significantly reduced in VSMCs isolated from the renal vasculature of FHH (2.4 ± 0.3%/cell, n = 6) vs. FHH. Add3 transgenic rats (11.4 ± 1.7%/cell, n = 6) consistent with disruption of the actin cytoskeleton. In addition, we observed the formation of an F‐actin net in primary renal VSMCs isolated from FHH rats, and reduced expression of the myosin regulatory light chains (MYL12A/B) that regulate actin polymerization and vascular contraction upon phosphorylation. These results suggest that down‐regulation of Add3 disrupts the actin cytoskeleton and the expression of MYL12A/B protein in renal VSMCs. These effects combine to impair the myogenic response of the Af‐art and autoregulation of renal blood flow. This increases transmission of pressure to the glomerulus, which contributes to the development of chronic kidney disease induced by hypertension in the FHH rat.Support or Funding InformationThis study was supported by grants HL36279 (RJR) and DK104184 (RJR), AG050049 (FF), P20GM104357 (RJR, FF ) from the National Institutes of Health; 16GRNT31200036 (FF) from the American Heart Association. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.