Research ArticleHypertension

Adducin- and Ouabain-Related Gene Variants Predict the Antihypertensive Activity of Rostafuroxin, Part 1: Experimental Studies

Science Translational Medicine  24 Nov 2010:
Vol. 2, Issue 59, pp. 59ra86
DOI: 10.1126/scitranslmed.3001815

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Help for Hypertension

As if changing its mind about how best to detoxify the body, the kidney first secretes a filtrate that contains almost everything in the blood but then recaptures much of it by pumping essential water, salts, and other molecules back in. The Na+, K+-ATPase, or sodium pump, recaptures sodium salts, and because Na+ is the prime determinant of extracellular fluid volume in the body, regulation of this pump controls blood pressure. Now a pair of papers describes how an antihypertension drug can correct abnormal sodium pumping and how this understanding of the drug’s mechanism points to a genetic signature that can predict whether a patient will respond to the drug.

One cause of hypertension is a particular variant(s) of the protein adducin, a modulator of protein exposure on the cell surface that stimulates the sodium pump; a second is high concentrations of endogenous ouabain, an activating ligand for the pump. Both factors abnormally enhance the pump function through the triggering of the Src signaling pathway. Rostafuroxin, a derivative of digitoxigenin, acts as an antihypertensive agent by interfering with both of these ways to activate the sodium pump, preventing an increase in renal tubular Na+ transport and the resulting hypertension.

In the first of the companion papers (Ferrandi et al.), the authors explore how rostafuroxin accomplishes its pressure-lowering feat. They show that the drug inhibits the Na+, K+ ATPase-Src-EGFR-ERK signaling activated by mutant adducin or ouabain, normalizing renal cell sodium transport, in two different rodent models of hypertension and in human cells. Upon closer examination of rostafurotoxin’(tm)s effects on Src-related phosphorylation in vitro, it became clear that the drug disrupts the ability of the variant adducin and the oubain-bound sodium pump to bind and activate Src at its SH2 domain.

In the second of the companion papers (Lanzani et al.), the authors apply these results to patients by examining genetic variants that control the mechanisms of hypertension explored in the first paper. Lanzani et al. inspected genetic alterations in genes that encode enzymes that control ouabain synthesis and transport as well as two variants of adducin. They then tested the ability of these genetic variants to predict the response to rostafuroxin in a group of never-before treated patients with hypertension. Individuals who carried certain combinations of these genetic variants responded well to rostofuroxin, displaying a mean drop in the placebo-corrected blood pressure of about 14 mmHg, a clinically meaningful value. The same genetic signature did not predict the blood pressure response to other antihypertensive drugs with different mechanisms of action. The authors suggest that this genetic signature may exist in about a quarter of hypertensive patients.

Finally, rostfuroxin may do more than lower blood pressure. Organ damage is known to be a downstream effect of an overactive Src signaling pathway — one of the byproducts of the hypertension mechanisms studied in this pair of papers. Because rostafuroxin interferes with Src signaling, the drug may curb the secondary damage to the heart, kidney, and brain caused by high blood pressure. Thus the kidney’s seemingly schizophrenic filtering actually represents a multilevel, fine-tuned control of the sodium pump as a means of managing blood pressure. Rostafuroxin can selectively correct hypertension in patients whose pumping mechanism is out of kilter, an advance toward personalized treatment of high blood pressure.

Footnotes

  • Citation: M. Ferrandi, I. Molinari, L. Torielli, G. Padoani, S. Salardi, M. P. Rastaldi, P. Ferrari, G. Bianchi, Adducin- and Ouabain-Related Gene Variants Predict the Antihypertensive Activity of Rostafuroxin. Part 1: Experimental Studies. Sci. Transl. Med. 2, 59ra86 (2010).