Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Rat chromosome 19 transfer from SHR ameliorates hypertension, salt-sensitivity, cardiovascular and renal organ damage in salt-sensitive Dahl rats Norbert Wendt a, , Angela Schulz a, , Anja-Kristin Siegel a , Judith Weiss a , Markus Wehland a , Anika Sietmann b , Peter Kossmehl a , Daniela Grimm a , Monika Stoll b and Reinhold Kreutz a Objectives Unlike Dahl salt-sensitive (SS) rats, some strains of spontaneously hypertensive (SHR) rats develop only minor organ damage even when exposed to high-salt diet. In previous linkage studies, we identified quantitative trait loci on rat chromosome 19 (RNO19) linked to the SHR allele suggesting a protective effect against salt-induced hypertensive organ damage in SS. Methods To test the relevance of this finding, we generated and characterized a consomic strain SS-19 SHR in which RNO19 from SHR was introgressed into the susceptible background of SS. We compared the effects of low-salt (0.2% NaCl) and high-salt (4% NaCl) diet exposure for 8 weeks on the development of hypertension and target organ damage in male consomic and SS animals (n U 14–20, each). Results Systolic blood pressure, relative left ventricular weight and urinary protein excretion were significantly lower in SS-19 SHR compared to SS under both low-salt and high-salt diet (P < 0.05, respectively). Left ventricular atrial natriuretic peptide mRNA expression showed a more pronounced 4.5-fold increase in SS compared to SS-19 SHR (two-fold) after high-salt (P < 0.05). In comparison to low diet, high-salt exposure induced a significant increase in vascular aortic hypertrophy index, left ventricular interstitial fibrosis (R210%) and perivascular fibrosis (R195%) in SS but not in consomic SS-19 SHR (P < 0.05, respectively). Conclusions These results demonstrate a strong protective effect of RNO19 from SHR on the development of hypertension, salt-sensitivity, cardiovascular and renal organ damage in SS. In particular, we demonstrate a genetic effect protecting against the development of cardiac fibrosis in salt-sensitive hypertension. J Hypertens 25:95– 102 Q 2007 Lippincott Williams & Wilkins. Journal of Hypertension 2007, 25:95–102 Keywords: genetics, hypertension, quantitative trait loci, rat, salt a Institut fu ¨ r Klinische Pharmakologie und Toxikologie, Campus Benjamin Franklin, Charite ´ – Universita ¨ tsmedizin Berlin, Berlin, Germany and b Leibniz-Institut fu ¨r Arterioskleroseforschung, Mu ¨ nster, Germany Correspondence and requests for reprints to Reinhold Kreutz, Department of Clinical Pharmacology and Toxicology, Charite ´ – Universita ¨ tsmedizin Berlin, Campus Benjamin Franklin, Hindenburgdamm 30, 12200 Berlin, Germany Tel: +49 30 84452280; fax: +49 30 84454482; e-mail: reinhold.kreutz@charite.de Sponsorship: Supported by the DFG (KR-1152-2/2, GRK 754) and by a grant from the Bundesministerium fu ¨ r Bildung und Forschung (Nationales Genomforschungsnetz: KGCV1, 01GS0416, NGFN2). Conflict of interest: none. Received 28 June 2006 Revised 16 August 2006 Accepted 1 September 2006 Introduction Primary (essential) hypertension is a multifactorial dis- ease with increasing prevalence worldwide [1]. It results from a complex interplay between genetic susceptibility and environmental factors [2]. Dietary salt intake represents one important factor contributing to hyper- tensive disease [3,4]. In addition, a significant proportion of patients with primary hypertension demonstrate significant changes of blood pressure in response to changes in salt intake and have thus been classified as salt-sensitive [5,6]. The clinical importance of salt-sensitive hypertension results from the observation that the prevalence is high and increases with age [7,8] and the more severe manifestation and progression of hypertensive target organ damage [4]. Thus, this disease phenotype is a major contributor to overall cardiovascular risk, particularly in ageing populations [4,9–11]. High-sodium intake and salt- sensitive hypertension are significant factors contributing to left ventricular hypertrophy (LVH) [12,13], vascular hypertrophy [14,15] and cardiovascular remodelling including cardiac fibrosis [16]. Therefore, it is a major contributor to cardiovascular disease [4,17]. High sodium intake and salt-sensitive blood pressure regulation may also affect the development of renal dysfunction and progression of chronic renal disease [4,18] and increased urinary albumin (UAE) rates have been associated with salt-sensitive hypertension [19,20]. Increased UAE identifies not only patients at increased risk for the devel- opment of renal failure, but also represents a strong pre- dictor for overall cardiovascular morbidity and mortality [21,22]. Original article 95  Both authors contributed equally to this work. 0263-6352 ß 2007 Lippincott Williams & Wilkins