Oxidants and Cardiorenal Vascular Remodeling—Insights from Rare Genetic Tubulopathies: Bartter’s and Gitelman’s Syndromes

Abstract

Two human genetic tubulopathies, Bartter’s (BS) and Gitelman’s (GS) syndromes, have normo/hypotension and absent cardiac remodeling despite their apparent angiotensin system (RAS) activation. This seeming contradiction has led to an extensive investigation of BSGS patients, the result of which is that BSGS represents a mirror image of hypertension. BSGS’s unique set of properties has then permitted their use as a human model to probe and characterize RAS system pathways and oxidative stress in cardiovascular and renal remodeling and pathophysiology. This review details the results using GSBS patients that provide a deeper understanding of Ang II signaling and its associated oxidants/oxidative stress in humans. By providing a more complete and complex picture of cardiovascular and renal remodeling pathways and processes, studies of GSBS can inform the identification and selection of new targets and therapies to treat these and other oxidant-related disorders.

The RAAS Goodfellas in Cardiovascular System

“…On the contrary, good glycemic control improved their effect ameliorating cardiac remodeling and enhancing the good branch of RAAS [102]. This is in line with the absence of cardiac remodeling observed in BS/GS patients [19]: indeed, they present low levels of glycosylated ACE2, probably due to their metabolic alkalosis and likely impairing the cellular glycosylation process [29].…”

“…Several studies from our group reported a strong activation of the ACE2/Ang 1-7/MasR axis in BS/GS patients, coupled with a reduced expression of proteins involved in the oxidative stress (as p22 phox ), reduced activation of the RhoA/Rho-kinase pathways, increase NO production and endothelial protection [15,18,19,78]. A comparative study between normotensive, hypertensive, and BS/GS patients reported that the p63RhoGEF, both at mRNA and protein level and MYPT-1 phosphorylation status were higher in hypertensive patients and lower in BS/GS patients compared to controls [79] (Figure 2).…”