ABSTRACT
BACKGROUND: Cyclosporine A (CsA) is an immunosuppressive drug used to prevent tissue allograft rejection. However, its long-term utilization is limited due to chronic nephrotoxicity for which no prevention is available. This study evaluated the effect of spironolactone on renal functional and structural alterations induced by CsA, and assessed whether the protective effect was associated with a reduction of transforming growth factor-beta (TGF-beta) and the change of extracellular matrix protein mRNA level. METHODS: Male Wistar rats fed with low sodium diet were divided in four treatment groups: vehicle, CsA (30 mg/kg), spironolactone (20 mg/kg), or CsA+spironolactone. After 21 days, creatinine clearance (CCr), blood CsA, arteriolopathy in renal tissue, and TGF-beta, collagen I, collagen IV, fibronectin, and epidermal growth factor (EGF) mRNA levels in renal cortex were determined. RESULTS: CsA reduced the CCr and up-regulated TGF-beta, collagen I and fibronectin mRNA expression with a significant development of arteriolopathy, and reduced EGF mRNA levels. In contrast, spironolactone administration prevented the fall in renal function and TGF-beta, collagen I, and fibronectin up-regulation, together with a reduction of arteriolopathy and tubulointerstitial fibrosis. CONCLUSION: Our data show that aldosterone plays an important role as a mediator of renal injury induced by CsA. Thus, mineralocorticoid receptor blockade may be a potential strategy to prevent CsA nephrotoxicity.
Subject(s)
Cyclosporine/toxicity , Immunosuppressive Agents/toxicity , Kidney Diseases/drug therapy , Mineralocorticoid Receptor Antagonists/therapeutic use , Spironolactone/therapeutic use , Aldosterone/physiology , Animals , Chronic Disease , Collagen Type I/genetics , Collagen Type IV/genetics , Fibronectins/genetics , Kidney/pathology , Kidney/physiopathology , Kidney Diseases/chemically induced , Kidney Diseases/physiopathology , Male , RNA, Messenger/analysis , Rats , Rats, Wistar , Transforming Growth Factor beta/genetics , Transforming Growth Factor beta1ABSTRACT
Rats that are administered angiotensin II (AngII) for 2 wk develop persistent salt-sensitive hypertension, which can be prevented by the immunosuppressor mycophenolate mofetil (MMF) given during the AngII infusion. This study examined the contribution of glomerular hemodynamics (GFR dynamics) in the post-AngII hypertensive response to a high-salt diet (HSD) and the effect of MMF treatment. During AngII administration, rats developed severe hypertension (systolic BP [SBP], 185 +/- 3.9 mmHg), proteinuria, afferent and efferent vasoconstriction, and glomerular hypertension. Rats that received AngII+MMF showed similar responses to AngII; however, they developed lower proteinuria (P < 0.05). At 2 wk, AngII was withdrawn and SBP returned toward normal. Rats were then placed on an HSD (4% NaCl), resulting in a progressive increase in SBP (155 +/- 8.2 mmHg at week 1 and 163 +/- 4.5 mmHg at week 5). GFR dynamic alterations persisted after AngII was stopped, i.e., afferent and efferent vasoconstriction, decreased glomerular plasma flow and single-nephron GFR, and lower ultrafiltration coefficient. These changes correlated with the thickening of the afferent arteriole and with focal tubulointerstitial injury. In the AngII+MMF group, SBP remained unchanged throughout the HSD period (146 +/- 2.3 mmHg at week 1 and 148 +/- 4.4 mmHg at week 5) in association with less afferent arteriolar thickening and tubulointerstitial injury. Single-nephron GFR, glomerular plasma flow, efferent resistance, and ultrafiltration coefficient returned to normal with a significant reduction in afferent resistance. These results suggest a critical role of cortical vasoconstriction in salt-sensitive hypertension. The MMF-induced prevention of these changes suggests that immune mechanisms are involved in the vasoconstrictive response.
Subject(s)
Angiotensin II/pharmacology , Hypertension/chemically induced , Hypertension/etiology , Immunosuppressive Agents/pharmacology , Kidney Cortex/blood supply , Mycophenolic Acid/analogs & derivatives , Sodium Chloride , Vasoconstriction/physiology , Animals , Drug Synergism , Hemodynamics/drug effects , Hypertension/pathology , Kidney/pathology , Kidney Glomerulus/blood supply , Male , Mycophenolic Acid/pharmacology , Rats , Rats, Sprague-DawleyABSTRACT
Los tumores primarios del corazón son raros. El más común es el mixoma, que es capaz de sintetizar IL-6 y con frecuencia tiene manifestaciones sistémicas, que confunden el diagnóstico. Los sarcomas cardiacos primarios, aún más raros, nunca han sido asociados a enfermedad sistémica. Informamos dos casos, en donde el diagnóstico presuntivo de lupus eritematoso sistémico fue modificado ante el hallazgo de sarcomas cardiacos primarios de estirpe muscular
Subject(s)
Humans , Male , Female , Adult , Heart Neoplasms/diagnosis , Heart Neoplasms/physiopathology , Lupus Erythematosus, Systemic/diagnosis , Sarcoma/diagnosis , Antibodies, Anticardiolipin , Diagnosis, DifferentialABSTRACT
Este reporte comprende el estudio histológico de 140 biopsias renales tomadas de 122 pacientes (109 mujeres y 13 varones) en quienes el diagnóstico de lupus eritematoso sistémico (LES) se estableció de acuerdo con los criterios del American College of Rheumatology (ACR) y el tiempo de evolución promedio fue de 3.5 años. En 103 se encontraron lesiones vasculares renales de uno o más tipos: necrosis, trombosis, leucocitoclasia, fibrosis, microangiopatía trombótica (MAT) y vasculitis necrosante. Se presenta la distribución por clase histológica y se analizan aquellos en quienes se encontró MAT. Se discute la importancia de la microangiopatía trombótica en LES como factor pronóstico y la posible relación clínica con anticuerpos anticardiolipina