OF WORK Our previous studies demontrated that two endogenous sodium pump ligands (SPL), ouabain-like compound and marinobufagenin, coexist in mammalian tissues. Unlike previously described SPL, MBG acts as a selective inhibitor of ouabain resistant alpha-1 isoform of Na/K-ATPase (NKA), the main sodium pump isoform in the kidney, vascular smooth muscle and adult myocardiocytes. During the last year, we continued studies of SPL in Dahl salt-sensitive rats (DS), in which the mutation of alpha-1 NKA and compensatory responses of SPL underlie development of NaCl sensitive hypertension. For the first time, we have demonstrated that HPLC purified endogenous MBG immunoreactive material from hypertensive DS potently inhibits the renal sodium pump (alpha-1 isoform) rather than alpha-3 NKA isoform (fetal rat brain). Further, in vivo administration of MBG antibody to DS blocked the elevations of blood pressure, natriuretic response and inhibition of renal sodium pump associated with NaCl loading. Thus, MBG fulfils the Koch's postulate for a putative natriuretic hormone involved in the pathogenesis of salt-sensitive hypertension. Previously, we have shown that protein kinase C (PKC) activation leads to enhanced sensitivity of the NKA to SPL. Our results demonstrate that the above potentiation occurs due to induction of regulatory phosphorylation of the NKA alpha-1 subunit. This PKC induced NKA phosphorylation is specific towards alpha-1 (vs. alpha-3) NKA isoform. Since both SPL and PKC interact on NKA activity, and both NKA and PKC are involved in hypertrophic signaling, we studied whether or not the modulatory interaction of PKC and MBG on alpha-1 NKA may be a target for therapeutic intervention in Dahl hypertension. The development of compensatory left ventricular hypertrophy (LVH) in DS on a high NaCl intake was associated with an upregulation of alpha-1 NKA, and PKC beta-II and delta in LV myocardium. Upregulated alpha-1 NKA exhibited enhanced sensitivity to MBG. Pretreatment of DS with cicletanine, an antihypertensive compound which directly inhibits the PKC, resulted in a decrease in blood pressure and LV weight and improvement of LV performance. LV alpha-1 NKA remained upregulated but exhibited less sensitivity to MBG. In parallel, cicletanine treatment prevented the upregulation of PKC beta-II and delta in LV sarcolemma.Thus, an endogenous ligand of alpha-1 NKA, MBG, is an important factor in pathogenesis of Dahl hypertension. Phosphorylation of alpha-1 NKA by PKC potentiates the effects of MBG. Therefore, a modulatory interaction of SPL and PKC beta-II and delta on NKA in cardiovascular tissues is a novel therapeutic target in NaCl sensitive hypertension.

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Fedorova, Larisa V; Raju, Vanamala; El-Okdi, Nasser et al. (2009) The cardiotonic steroid hormone marinobufagenin induces renal fibrosis: implication of epithelial-to-mesenchymal transition. Am J Physiol Renal Physiol 296:F922-34
Fedorova, Olga V; Simbirtsev, Andrey S; Kolodkin, Nikolai I et al. (2008) Monoclonal antibody to an endogenous bufadienolide, marinobufagenin, reverses preeclampsia-induced Na/K-ATPase inhibition and lowers blood pressure in NaCl-sensitive hypertension. J Hypertens 26:2414-25
Kennedy, David J; Elkareh, Jihad; Shidyak, Amjad et al. (2008) Partial nephrectomy as a model for uremic cardiomyopathy in the mouse. Am J Physiol Renal Physiol 294:F450-4
Bagrov, Alexei Y; Shapiro, Joseph I (2008) Endogenous digitalis: pathophysiologic roles and therapeutic applications. Nat Clin Pract Nephrol 4:378-92
Kashkin, Vladimir A; Zvartau, Edwin E; Fedorova, Olga V et al. (2008) Endogenous bufadienolide mediates pressor response to ethanol withdrawal in rats. Eur Neuropsychopharmacol 18:74-7
Anderson, David E; Fedorova, Olga V; Morrell, Christopher H et al. (2008) Endogenous sodium pump inhibitors and age-associated increases in salt sensitivity of blood pressure in normotensives. Am J Physiol Regul Integr Comp Physiol 294:R1248-54
Bagrov, Yakov Y; Manusova, Natalia B; Frolova, Elena V et al. (2007) Endogenous sodium pump inhibitors, diabetes mellitus and preeclampsia Preliminary observations and a hypothesis. Pathophysiology 14:147-51
Fedorova, Olga V; Zhuravin, Igor A; Agalakova, Natalia I et al. (2007) Intrahippocampal microinjection of an exquisitely low dose of ouabain mimics NaCl loading and stimulates a bufadienolide Na/K-ATPase inhibitor. J Hypertens 25:1834-44
Elkareh, Jihad; Kennedy, David J; Yashaswi, Belvadi et al. (2007) Marinobufagenin stimulates fibroblast collagen production and causes fibrosis in experimental uremic cardiomyopathy. Hypertension 49:215-24
Kennedy, David J; Vetteth, Sandeep; Periyasamy, Sankaridrug M et al. (2006) Central role for the cardiotonic steroid marinobufagenin in the pathogenesis of experimental uremic cardiomyopathy. Hypertension 47:488-95

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