We recommend to include in the FXTAS testing guidelines both CCS hyperintensity and peripheral neuropathy and to consider them as new major radiologic and minor clinical criterion, respectively, for the diagnosis of FXTAS. FXTAS should also be considered in women or when tremor, MCP hyperintensities, or family history of FXS are lacking. Our study broadens the spectrum of tremor, peripheral neuropathy, and MRI abnormalities in FXTAS, hence revealing the need for revised criteria.

Abstract. Renal fibrosis is one of the major complications associated with the development of hypertension. The objective of the present study was to determine whether and by which mechanisms treatment with AT1 receptor antagonists makes possible the regression of renal vascular and glomerular fibrosis. Experiments were performed in the hypertensive model of nitric oxide (NO) deficiency in rats. After 4 wk of hypertension, mortality rates averaged 20%; the surviving animals displayed a decline of renal function (urine protein/ creatinine, 1.89 Ϯ 0.63 versus 0.24 Ϯ 0.03 mg/mmol; creatininemia, 110 Ϯ 14 versus 38 Ϯ 2 mmol/L in hypertensive animals and control, respectively; P Ͻ 0.01) and an exaggerated gene and protein expression of TGF-␤, collagen I, and collagen IV (P Ͻ 0.001) within the renal vasculature associated with the development of glomerulosclerosis (sclerotic index, 2.26 Ϯ 0.29 versus 0.12 Ϯ 0.04; P Ͻ 0.001). In addition, activities of matrix metalloproteinases 2 and 9 were increased twofold in renal vessels and glomeruli (P Ͻ 0.01).Afterwards, losartan, an antagonist of angiotensin receptor type I, or hydralazine were administered in subgroups of hypertensive animals. After 1 wk of angiotensin II antagonism, collagen I, collagen IV, and TGF-␤ gene and protein expressions were decreased and glomerulosclerosis was less marked (sclerotic index 1.04 Ϯ 0.45), whereas activities of metalloproteinases remained twofold higher than controls (P Ͻ 0.01). Hydralazine failed to improve renal function despite a similar degree of systolic pressure decrease. After 4 wk of losartan, the renal functional and histologic parameters were completely normalized, whereas they remained damaged in the hypertensive animals in which the mortality rate reached 85%. These data suggest that the progression of renal vascular fibrosis is a reversible process, at least in the NO deficiency model. The mechanism of the regression appears to be dual: inhibition of collagen synthesis due to AT1 receptor antagonism and activation of metalloproteinases that is probably associated with the degree of fibrosis independently of AT1 blockade.Development of renal sclerotic lesions is one of the most common complications of hypertension. This pathophysiologic process is associated with changes in the structure of renal vasculature due to abnormal accumulation of extracellular matrix (particularly collagen types I, III, and IV) in renal resistance vessels, glomeruli, and interstitium (1). Although recent data obtained in the cardiac tissue indicate that the development of cardiac fibrosis is a reversible process under certain circumstances and treatments (blockade of angiotensin-converting enzyme [ACE] or antagonism of AT1 receptor) (2), very little is known about the capability of the renal vasculature to recover after the development of fibrotic injury.In previous studies, we investigated the role of angiotensin II (AngII) in the mechanisms leading to the development of renal vascular and glomerular fibrosis using a strain of transgenic mice tha...

Patients with sickle-cell disease (SCD) suffer from tissue damage and life-threatening complications caused by vasoocclusive crisis (VOC). Endothelin receptors (ETRs) are mediators of one of the most potent vasoconstrictor pathways in mammals, but the relationship between vasoconstriction and VOC is not well understood. We report here that pharmacological inhibition of ETRs prevented hypoxia-induced acute VOC and organ damage in a mouse model of SCD. An in vivo ultrasonographic study of renal hemodynamics showed a substantial increase in endothelin-mediated vascular resistance during hypoxia/reoxygenation-induced VOC. This increase was reversed by administration of the dual ETR antagonist (ETRA) bosentan, which had pleiotropic beneficial effects in vivo. It prevented renal and pulmonary microvascular congestion, systemic inflammation, dense rbc formation, and infiltration of activated neutrophils into tissues with subsequent nitrative stress. Bosentan also prevented death of sickle-cell mice exposed to a severe hypoxic challenge. These findings in mice suggest that ETRA could be a potential new therapy for SCD, as it may prevent acute VOC and limit organ damage in sickle-cell patients.

A frequent complication of hypertension is the development of chronic renal failure. This pathology usually is initiated by inflammatory events and is characterized by the abnormal accumulation of collagens within the renal tissue. The purpose of this study was to investigate the role of discoidin domain receptor 1 (DDR1), a nonintegrin collagen receptor that displays tyrosine-kinase activity, in the development of renal fibrosis. To this end, hypertension was induced with angiotensin in mice that were genetically deficient of DDR1 and in wild-type controls. After 4 or 6 wk of angiotensin II administration, wild-type mice developed hypertension that was associated with perivascular inflammation, glomerular sclerosis, and proteinuria. Systolic pressure increase was similar in the DDR1-deficient mice, but the histologic lesions of glomerular fibrosis and inflammation were significantly blunted and proteinuria was markedly prevented. Immunostaining for lymphocytes, macrophages, and collagens I and IV was prominent in the renal cortex of wild-type mice but substantially reduced in DDR1 null mice. In separate experiments, renal cortical slices of DDR1 null mice showed a blunted response of chemokines to LPS that was accompanied by a considerable protection against the LPS-induced mortality. These results indicate the importance of DDR1 in mediating inflammation and fibrosis. Use of DDR1 inhibitors could provide a completely novel therapeutic approach against diseases that have these combined pathologies. H ypertension frequently is complicated by the development of chronic renal failure, a complex pathology that is initiated by inflammatory events that evolve to increased synthesis and accumulation of extracellular matrix (ECM; mainly collagens) within the renal tissue and lead over time to loss of function and ESRD. To date, no efficient treatment that can stop or, even more desirable, reverse the decline of renal function exists. Therefore, the understanding of the systems and/or mechanisms that are involved in the development of renal vascular inflammation and fibrosis will provide valuable information to design specific pharmacologic targets to treat this incurable disease.Important advancements have been made regarding the mechanisms that are involved in the development of chronic renal failure. These studies focused mainly in the systems or agents that promote ECM synthesis and progression of renal disease. We and other investigators, for instance, clearly identified and characterized the signaling pathways that vasoconstrictor peptides are using to activate collagen synthesis (1-4). Less is known about the mechanisms regarding the postsynthesis regulation of ECM, such as matrix anchoring and interactions with the cell membrane.Among the systems that interact with the ECM are the discoidin domain receptors (DDR). They are the first identified receptor tyrosine kinases that bind directly to the ECM (5). DDR1 binds all types of collagens and is widely expressed in a variety of tissues, including vascular smooth m...