Markus Bieringer

Mineralocorticoid Receptor Affects AP-1 and Nuclear Factor-κB Activation in Angiotensin II–Induced Cardiac Injury

Aldosterone is implicated in cardiac hypertrophy and fibrosis. We tested the role of the mineralocorticoid receptor in a model of angiotensin II–induced cardiac injury. We administered spironolactone (SPIRO; 20 mg · kg−1 · d−1), valsartan (VAL; 10 mg · kg−1 · d−1), or vehicle to rats double transgenic for the human renin and angiotensinogen genes (dTGR). We investigated basic fibroblast growth factor (bFGF), platelet-derived growth factor, transforming growth factor-&bgr;1, and the transcription factors AP-1 and nuclear factor (NF)-&kgr;B. We used immunohistochemistry, electrophoretic mobility shift assays, and TaqMan RT-PCR. Untreated dTGR developed hypertension, cardiac hypertrophy, vasculopathy, and fibrosis with a 50% mortality rates at 7 weeks. SPIRO and VAL prevented death and reversed cardiac hypertrophy, while only VAL normalized blood pressure. Both drugs prevented vasculopathy. bFGF was markedly upregulated in dTGR, whereas platelet-derived growth factor-B and transforming growth factor-&bgr;1 were little changed. VAL and SPIRO suppressed this upregulation. Both AP-1 and NF-&kgr;B were activated in dTGR compared with controls. VAL and SPIRO reduced both transcription factors and reduced bFGF, collagen I, fibronectin, and laminin in the interstitium. These findings show that aldosterone promotes hypertrophy, cardiac remodeling, and fibrosis, independent of blood pressure. The effects involve AP-1, NF-&kgr;B, and bFGF. Mineralocorticoid receptor blockade downregulates these effectors and reduces angiotensin II–induced cardiac damage.

Cyclosporin A Protects Against Angiotensin II–Induced End-Organ Damage in Double Transgenic Rats Harboring Human Renin and Angiotensinogen Genes

Leukocyte infiltration and adhesion molecule activation play a central role in the pathogenesis of angiotensin II (Ang II)-induced end-organ damage in double transgenic rats (dTGR) harboring human renin and angiotensinogen genes. We tested the hypothesis that the immunosuppressive agent cyclosporine (CsA) protects against the Ang II-induced myocardial and renal damage in dTGR. Furthermore, we investigated the influence of CsA on interleukin-6 (IL-6) and inducible nitric oxide synthase (iNOS) expression and the DNA binding activity of transcription factor necrosis factor-kappaB (NF-kappaB). The 4-week-old rats were divided into 4 groups: (1) control dTGR (n=20), (2) dTGR plus CsA (5 mg/kg SC for 3 weeks, n=15), (3) normotensive Sprague-Dawley (SD) rats (n=10), and (4) SD rats plus CsA (n=8). In dTGR, CsA completely prevented cardiovascular death (0 of 15 versus 9 of 20), decreased 24-hour albuminuria by 90% and systolic blood pressure by 35 mm Hg, and protected against the development of cardiac hypertrophy. Whole blood CsA concentrations 24 hours after the last drug treatment were 850+/-15 ng/mL. Semiquantitative ED-1 and Ki-67 (a nuclear cell proliferation-associated antigen) scoring showed that CsA prevented perivascular monocyte/macrophage infiltration and prevented cell proliferation in the kidneys and hearts of dTGR, respectively. The beneficial effects of CsA were, at least in part, mediated by the suppression of IL-6 and iNOS expression. Electrophoretic mobility shift assay revealed that CsA regulated inflammatory response in part through the NF-kappaB transcriptional pathway. In contrast to dTGR, CsA increased blood pressure in normotensive SD rats by 10 mm Hg and had no effect on cardiac mass or 24-hour urinary albumin excretion. Perivascular monocyte/macrophage infiltration, IL-6, and iNOS expression or cell proliferation were not affected by CsA in SD rats. Our findings indicate that CsA protects against Ang II-induced end-organ damage and underscore the central role of vascular inflammatory response in the pathogenesis of myocardial and renal damage in dTGR. The beneficial effects of CsA in the kidney and heart are mediated, at least in part, by suppression of IL-6 and iNOS expression via NF-kappaB transcriptional pathway.

Kaliopenic nephropathy revisited

In the ‘older’ literature, a definitive renal pathology was described in patients with long-standing hypokalaemia and depletion of the bodys potassium reserves. The topic is relevant because possibly a quite cheaply reversible element in the course of chronic kidney disease progression could be addressed. Earlier, pathologists drew attention to vacuolar changes in renal tubular epithelium accompanied by inflammatory interstitial changes in patients with potassium losses. The diagnostic term ‘kaliopenic nephropathy’ was coined to describe such patients. Kaliopenic nephropathy now receives less emphasis than in earlier times. However, with eating disorders, laxative abuse and other potential causes, we suggest that the syndrome should be resurrected.

A cardiorenal-pulmonary-cutaneous-muscle syndrome

Anti-synthetase syndrome is a relatively recently described auto-immune disease characterized by auto-antibodies to enzymes that acetylate transfer RNA (tRNA). Interstitial pulmonary disease and inflammatory myopathy are regular findings. Our patient also exhibited a lupus-like glomerulonephritis. An important clue was the presence of ‘mechanics’ hands. Nephrologists need to be aware of this syndrome.

Spironolactone Ameliorates Angiotensin Ii-Induced Renal Damage Via the Inhibition of Ap-1 and Nf-κB

P168 Recently, clinical trials have demonstrated the efficacy of spironolactone (SPIRO) in men. Nevertheless the molecular mechanism of action not completely understood. Locally generated angiotensin II (ANG II) stimulates aldosterone. Therefore, we have tested the hypothesis that SPIRO ameliorates ANG II-induced renal damage. Furthermore, we investigated the effect of SPIRO on the transcription factors AP-1 and NF-κB. We treated transgenic rats overexpressing the human renin and angiotensinogen genes (dTGR) from week 5 to 7 with SPIRO (20 mg/kg/d). Plasma aldosterone was significantly increased in dTGR vs. SPIRO treated and non-transgenic (SD) rats (p