Effects of simvastatin and sildenafil on NHE3 activity

• Grant number: 13/16751-5
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: March 01, 2014
• End date: July 31, 2016
• Field of knowledge: Biological Sciences - Physiology - Physiology of Organs and Systems
• Principal Investigator: Gerhard Malnic
• Grantee: Priscilla Marys Costa dos Santos
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

The drugs Sildenafil and Simvastatin modulate the activity of proteins and molecules involved in intracellular signaling. Simvastatin is a molecule of the statins family, which are inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase. In addition to this function, it's also currently assigned to Simvastatin via an inhibitory effect on the GTPase Rho (family of proteins that includes Rac1, Cdc42 and RhoA) and accessory proteins. Sildenafil is an inhibitor of PDE5, a cGMP phosphodiesterase. In the kidney tissue both Rho GTPase and PDE5 are expressed and have physiological and pathophysiological roles. Recent studies have found that these drugs increase aquaporin 2 (AQP2) insertion in the collecting duct of Brattleboro rats (model with neurogenic diabetes insipidus). The effects of Simvastatin is accompanied by water retention, increased of urinary osmolarity and decreased urinary flow. However, Sidenafil is not capable of increasing osmolality and reducing the flow of urine in these animals (Bouley et al, 2005; Li et al, 2011). It is believed that the use of Sildenafil promotes the insertion of AQ2 in collector duct and natriuresis, which could antagonize the anti-diuretic effect produced by apical insertion of aquaporins. However, there is no study that has determined the transport mechanism involved in the retention or excretion of Na+ to the treatment with Simvastatin and Sildenafil, respectively. In the kidney, the proximal tubule is the place where 70% of filtered sodium throughout the day is reabsorbed. The load of sodium is reabsorbed by NHE3 and its physiological importance for the regulation of extracellular volume became evident after the development of knockout mice for this protein. The objective of the present work is to determine whether Simvastatin promotes sodium and volume retention by stimulating NHE3; while Sildenafil promotes sodium excretion, natriuresis and volume loss by inhibiting NHE3 in renal tubules in vivo and OKP cells culture. We also intend to determine the molecular mechanisms by which these drugs modulate this important protein related to the volume homeostasis, such as: 1) the intracellular signaling pathways involved; 2) addiction modulating exocytosis and/or endocytosis of NHE3; 3) modulation of the turnover. We also intend to investigate whether treatment with these drugs can alter the renal excretion of water and sodium in vivo, and other carriers Na+ cast along of nephron are involved in natriuresis (promoted by Sildenafil) or sodium retention (involved in the effects of Simvastatin), such as the ENaC and NKCC.

Academic Publications

(References retrieved automatically from State of São Paulo Research Institutions)

SANTOS, Priscilla Marys Costa dos. Effects of simvastatin and sildenafil on NHE3 activity in proximal tubes of wistar rats.. 2017. Doctoral Thesis - Universidade de São Paulo (USP). Instituto de Ciências Biomédicas (ICB/SDI) São Paulo.