Actions of the dual FAAH/MAGL inhibitor JZL195 in a murine inflammatory pain model.

The analgesic efficacy of cannabinoids in chronic pain models is limited by side-effects. It has been proposed that this might be overcome by using agents which indirectly activate the endocannabinoid system. We examined the analgesic and side-effect profile of the dual FAAH/MAGL inhibitor JZL195 in an inflammatory pain model. The effect of systemic injections of a range of doses of JZL195 and the pan-cannabinoid receptor agonist WIN55212 were performed 1 day following intraplantar injection of CFA in C57BL/6 mice. JZL195 and WIN55212 both reduced mechanical allodynia and thermal hyperalgesia, and produced catalepsy and sedation in a dose dependent manner. Unlike WIN55212, JZL195 reduced allodynia at doses below those at which side-effects were observed. The effects of JZL195 and WIN55212 were abolished by co-application with the CB1 antagonist AM251. The CB2 antagonist also reduced the JZL195 anti-allodynia, and reversed the WIN55212 anti-allodynia. The reduction in allodynia produced by JZL195 was greater than that produced individually by the FAAH and MAGL inhibitors, URB597 and JZL184. These findings suggest that JZL195 reduces inflammation induced allodynia at doses below those which produce side-effects, and displays greater efficacy that FAAH or MAGL inhibitors. Thus, dual FAAH/MAGL inhibition has the potential to alleviate inflammatory pain with reduced cannabinoid-like side-effects.

Upregulation and intrarenal redistribution of heat shock proteins 90alpha and 90beta by low-sodium diet in the rat.

Two genes encoding isoforms heat shock protein (Hsp) 90alpha and Hsp90beta constitute the Hsp90 subfamily. In addition to their role in regulating mineralocorticoid and glucocorticoid receptors, these proteins have been associated with nitric oxide production. However, little is known regarding Hsp90 isoform expression and regulation in kidney. In this study we characterized the expression and localization of Hsp90 isoforms and evaluated the influence of low-sodium intake on their expression and distribution in kidney by using reverse transcription-polymerase chain reaction, Western blot, and immunohistochemistry techniques. We found that Hsp90alpha and Hsp90beta were expressed abundantly in both the renal cortex and the medulla; however, Hsp90 isoform expression was higher in the medulla than in the cortex. Immunohistochemistry of Hsp90alpha and Hsp90beta showed intense staining in the apical membrane of proximal and distal tubules. In the outer cortex these proteins were localized intracytosolically, whereas in the inner renal medulla they were restricted mainly to the basolateral membrane. Expression of Hsp9alpha and Hsp90beta was upregulated in the renal cortex during sodium restriction. In addition, both proteins exhibited redistribution from the cytoplasm to the basolateral side in thick ascending limb cells when rats were fed with a low-salt diet. Our results showed that Hsp90alpha and Hsp90beta were expressed abundantly in renal tissue. Expression and localization patterns under normal and salt-restricted intake were different between the cortex and the medulla, suggesting that these proteins may be involved in different processes along the nephron. Hsp90alpha and Hsp90beta upregulation induced by a low-sodium diet together with redistribution in thick ascending limb cells suggests that Hsp90 plays a role in the modulation of sodium reabsorption under these circumstances.

Therapeutic benefit of spironolactone in experimental chronic cyclosporine A nephrotoxicity.

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.

Renal cortical vasoconstriction contributes to development of salt-sensitive hypertension after angiotensin II exposure.

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.

El sarcoma cardiaco ¿simula lupus eritematoso y vasculitis? Informe de 2 casos / Heart sarcoma mimicks systemic lupus erythematosus? Report of 2 cases

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

Importancia de las lesiones vasculares microangiopáticas en pacientes con nefritis lúpica / Lesions vascular microangiopathy in patients with systemic lupus erithematosus

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