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Objective: Increased urinary albumin excretion (UAE) represents an independent cardiovascular risk factor in the general population and particularly in patients with diabetes or arterial hypertension. It has been suggested that increased UAE may be related to a generalized endothelial dysfunction. We set out to identify candidate genes for increased UAE by glomerular transcriptome analysis in the Munich Wistar Frömter (MWF) genetic rat model with spontaneous hypertension and albuminuria., Methods: First, we performed microarray expression analysis in isolated glomerular tissue in MWF with established albuminuria and normal Wistar rats. Second, in validation experiments and follow-up studies we focused on the identified upregulation of glomerular complement component C1q expression in MWF., Results: Overall, 38 genes with a regulation score > 2 were differentially expressed in glomerular RNA. Quantitative real-time reverse transcriptase-polymerase chain reaction (RT-PCR), in-situ hybridization and immunohistochemistry analysis revealed that C1q is indeed significantly upregulated in the glomerulus of MWF. Additionally, CD24, although not detected by the microarray experiment, was found to be differentially expressed in MWF glomeruli using quantitative real-time RT-PCR and immunohistochemstry. Interestingly, we could show for the first time that the glomerular endothelium represents the site of increased C1q and CD24 expression in MWF. In contrast, endothelial expression of this gene is low or absent in normotensive Wistar and in spontaneously hypertensive rats (SHR) without albuminuria., Conclusions: The induction of C1q and CD24 expression confined to the glomerular endothelium might represent a possible repair mechanism of the capillary wall damage.

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-19SHR 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=14-20, each)., Results: Systolic blood pressure, relative left ventricular weight and urinary protein excretion were significantly lower in SS-19SHR 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 (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 (+210%) and perivascular fibrosis (+195%) in SS but not in consomic SS-19SHR (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.