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Ferrandi M.,Prassis Sigma Tau Research Institute | Molinari I.,Prassis Sigma Tau Research Institute | Torielli L.,Prassis Sigma Tau Research Institute | Padoani G.,Prassis Sigma Tau Research Institute | And 5 more authors.
Science Translational Medicine | Year: 2010

Essential hypertension is a complex, multifactorial disease associated with a high cardiovascular risk and whose genetic-molecular basis is heterogeneous and largely unknown. Although multiple antihypertensive therapies are available, the large individual variability in drug response results in only a modest reduction of the cardiovascular risk and unsatisfactory control of blood pressure in the hypertensive population as a whole. Two mechanisms, among others, are associated with essential hypertension and related organ damage: mutant α-adducin variants and high concentrations of endogenous ouabain. An antihypertensive agent, rostafuroxin, selectively inhibits these mechanisms in rodents. We investigated the molecular and functional effects of mutant α-adducin, ouabain, and rostafuroxin in hypertensive rats, human cells, and cell-free systems and demonstrated that both mutant α-adducin variants and the ouabain-Na,K-ATPase (Na+- and K+-dependent adenosine triphosphatase) complex can interact with the Src-SH2 (Src homology 2) domain, increasing Src activity and the Src-dependent Na,K-ATPase phosphorylation and activity. Wild-type α-adducin or Na,K-ATPase in the absence of ouabain showed no interaction with the Src-SH2 domain. Rostafuroxin disrupted the interactions between the Src-SH2 domain and mutant α-adducin or the ouabain-Na,K-ATPase complex and blunted Src activation and Na,K-ATPase phosphorylation, resulting in blood pressure normalization in the hypertensive rats. We have also shown the translatability of these data to humans in a pharmacogenomic clinical trial, as described in the companion paper. Source


Rolla D.,Azienda Ospedaliera Universitaria San Martino | Bellino D.,Azienda Ospedaliera Universitaria San Martino | Peloso G.,Azienda Ospedaliera Universitaria San Martino | Rastaldi M.P.,Laboratorio Of Ricerca Nefrologica | And 2 more authors.
Journal of Nephropathology | Year: 2013

Background: Recently, Mikulicz’s disease has been defined as an IgG-4 related disease, a systemic condition, where the hallmark pathology findings are lymphoplasmacytic infiltrates, immunoglobulin (Ig)G4-positive plasma cells, modest tissue eosinophilia, and intense fibrosis. Case: We present a case of 63-year-old man who showed epigastralgia and elevated serum lipase levels. Computed tomography of the abdomen revealed a bulky mass of the pancreas, so he underwent bilious-digestive anastomosis, and biopsy of the pancreas revealed massive infiltration of lymphocytes and plasma cells. The patient was therefore diagnosed with sclerosing chronic pancreatitis (Kuttner’s tumour). After one year, the patient began to exhibit signs of “sicca syndrome”, and at the same time, he demonstrated progressive renal failure. Immunological tests showed hypocomplementemia, and the renal biopsy specimen demonstrated interstitial inflammation, in which infiltrate was composed of lymphocytes, while infiltrating plasma cells showed immunoreactivity to IgG4. Sialography revealed severe involvement of the salivary glands, and Schirmer’s test resulted positive. Conclusions: Here, we report successful treatment of the first case in Italy of a patient with hypocomplementemic tubulointerstitial nephritis in IgG4-related disease. © 2013, Society of Diabetic Nephropathy Prevention. All rights reserved. Source


Ferrandi M.,Prassis Sigma Tau Research Institute | Cusi D.,University of Milan | Cusi D.,Fondazione Filarete | Molinari I.,Prassis Sigma Tau Research Institute | And 19 more authors.
Journal of Molecular Medicine | Year: 2010

Adducins are cytoskeletal actin-binding proteins (α, β, γ) that function as heterodimers and heterotetramers and are encoded by distinct genes. Experimental and clinical evidence implicates α- and β-adducin variants in hypertension and renal dysfunction. Here, we have addressed the role of α- and β-adducin on glomerular function and disease using β-adducin null mice, congenic substrains for α- and β-adducin from the Milan hypertensive (MHS) and Milan normotensive (MNS) rats and patients with IgA nephropathy. Targeted deletion of β-adducin in mice reduced urinary protein excretion, preceded by an increase of podocyte protein expression (phospho-nephrin, synaptopodin, α-actinin, ZO-1, Fyn). The introgression of polymorphic MHS β-adducin locus into MNS (Add2, 529R) rats was associated with an early reduction of podocyte protein expression (nephrin, synaptopodin, α-actinin, ZO-1, podocin, Fyn), followed by severe glomerular and interstitial lesions and increased urinary protein excretion. These alterations were markedly attenuated when the polymorphic MHS α-adducin locus was also present (Add1, 316Y). In patients with IgA nephropathy, the rate of decline of renal function over time was associated to polymorphic β-adducin (ADD2, 1797T, rs4984) with a significant interaction with α-adducin (ADD1, 460W, rs4961). These findings suggest that adducin genetic variants participate in the development of glomerular lesions by modulating the expression of specific podocyte proteins. Source


Ju W.,University of Michigan | Greene C.S.,Princeton University | Eichinger F.,University of Michigan | Nair V.,University of Michigan | And 11 more authors.
Genome Research | Year: 2013

Cell-lineage-specific transcripts are essential for differentiated tissue function, implicated in hereditary organ failure, and mediate acquired chronic diseases. However, experimental identification of cell-lineage-specific genes in a genome-scale manner is infeasible for most solid human tissues. We developed the first genome-scale method to identify genes with celllineage-specific expression, even in lineages not separable by experimental microdissection. Our machine-learning-based approach leverages high-throughput data from tissue homogenates in a novel iterative statistical framework. We applied this method to chronic kidney disease and identified transcripts specific to podocytes, key cells in the glomerular filter responsible for hereditary and most acquired glomerular kidney disease. In a systematic evaluation of our predictions by immunohistochemistry, our in silico approach was significantly more accurate (65% accuracy in human) than predictions based on direct measurement of in vivo fluorescence-tagged murine podocytes (23%). Our method identified genes implicated as causal in hereditary glomerular disease and involved in molecular pathways of acquired and chronic renal diseases. Furthermore, based on expression analysis of human kidney disease biopsies, we demonstrated that expression of the podocyte genes identified by our approach is significantly related to the degree of renal impairment in patients. Our approach is broadly applicable to define lineage specificity in both cell physiology and human disease contexts. We provide a user-friendly website that enables researchers to apply this method to any cell-lineage or tissue of interest. Identified cell-lineage-specific transcripts are expected to play essential tissue-specific roles in organogenesis and disease and can provide starting points for the development of organ-specific diagnostics and therapies. © 2013 Mesner et al. Source

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