Francesco Trepiccione

Bio: Francesco Trepiccione is an academic researcher from Seconda Università degli Studi di Napoli. The author has contributed to research in topics: Medicine & Kidney. The author has an hindex of 22, co-authored 79 publications receiving 1087 citations. Previous affiliations of Francesco Trepiccione include Paris Descartes University & French Institute of Health and Medical Research.

Renal Atp6ap2/(Pro)renin Receptor Is Required for Normal Vacuolar H+-ATPase Function but Not for the Renin-Angiotensin System

Abstract: ATPase H+-transporting lysosomal accessory protein 2 (Atp6ap2), also known as the (pro)renin receptor, is a type 1 transmembrane protein and an accessory subunit of the vacuolar H+-ATPase (V-ATPase) that may also function within the renin-angiotensin system. However, the contribution of Atp6ap2 to renin-angiotensin-dependent functions remains unconfirmed. Using mice with an inducible conditional deletion of Atp6ap2 in mouse renal epithelial cells, we found that decreased V-ATPase expression and activity in the intercalated cells of the collecting duct impaired acid-base regulation by the kidney. In addition, these mice suffered from marked polyuria resistant to desmopressin administration. Immunoblotting revealed downregulation of the medullary Na+-K+-2Cl- cotransporter NKCC2 in these mice compared with wild-type mice, an effect accompanied by a hypotonic medullary interstitium and impaired countercurrent multiplication. This phenotype correlated with strong autophagic defects in epithelial cells of medullary tubules. Notably, cells with high accumulation of the autophagosomal substrate p62 displayed the strongest reduction of NKCC2 expression. Finally, nephron-specific Atp6ap2 depletion did not affect angiotensin II production, angiotensin II-dependent BP regulation, or sodium handling in the kidney. Taken together, our results show that nephron-specific deletion of Atp6ap2 does not affect the renin-angiotensin system but causes a combination of renal concentration defects and distal renal tubular acidosis as a result of impaired V-ATPase activity.

Treatment and long-Term outcome in primary distal renal tubular acidosis

Abstract: Background: Primary distal renal tubular acidosis (dRTA) is a rare disorder, and we aimed to gather data on treatment and long-term outcome. / Methods: We contacted paediatric and adult nephrologists through European professional organizations. Responding clinicians entered demographic, biochemical, genetic and clinical data in an online form. / Results: Adequate data were collected on 340 patients (29 countries, female 52%). Mutation testing had been performed on 206 patients (61%); pathogenic mutations were identified in 170 patients (83%). The median (range) presentation age was 0.5 (0–54) years and age at last follow-up was 11.0 (0–70.0) years. Adult height was slightly below average with a mean (SD score) of −0.57 (±1.16). There was an increased prevalence of chronic kidney disease (CKD) Stage ≥2 in children (35%) and adults (82%). Nephrocalcinosis was reported in 88%. Nephrolithiasis was more common with SLC4A1 mutations (42% versus 21%). Thirty-six percent had hearing loss, particularly in ATP6V1B1 (88%). The median (interquartile range) prescribed dose of alkali (mEq/kg/day) was 1.9 (1.2–3.3). Adequate metabolic control (normal plasma bicarbonate and normocalciuria) was achieved in 158 patients (51%), more commonly in countries with higher gross domestic product (67% versus 23%), and was associated with higher height and estimated glomerular filtration rate. / Conclusion: Long-term follow-up from this large dRTA cohort shows an overall favourable outcome with normal adult height for most and no patient with CKD Stage 5. However, 82% of adult patients have CKD Stages 2–4. Importance of adequate metabolic control was highlighted by better growth and renal function but was achieved in only half of patients.

Lithium-induced nephrogenic diabetes insipidus: new clinical and experimental findings.

Abstract: Lithium (Li+) salts are widely used to treat bipolar mood disorders. Recent trials suggest a potential efficacy also in the treatment of amyotrophic lateral sclerosis and Alzheimer's disease. Li+ is freely filtered by the glomerulus and mainly reabsorbed in the proximal convoluted tubule. Reabsorption in the distal nephron becomes significant under sodium-restricted conditions. Nevertheless, the distal nephron is greatly affected by Li+ even under normal sodium intake. Polyuria, renal tubular acidosis and finally chronic renal failure are the most frequent adverse effects. The occurrence of an overt nephrogenic diabetes insipidus (NDI) limits Li+ usage and imposes suspension. The molecular mechanisms of Li+-related urinary concentration defect involve a dysregulation of the aquaporin system in principal cells of the collecting duct. ENaC is crucial as the entry route for intracellular Li+ accumulation. The basolateral exit route is not clearly identified, but some evidence suggests Na+/H+ exchanger 1 (NHE1) as a potential candidate. Li+ promotes polyuria mainly counteracting the intracellular vasopressin signaling. An additional role of the inner medullary interstitial cells and PGE-2 pathway has to be considered. The GSK3s cascade is also regulated by Li+. GSK3s inhibition could lead not only to the polyuria, but also to the Li+-dependent proliferative effect on principal cells. Cellular reorganization of the collecting duct and microcysts are the main pathological findings during Li+ treatment. Their relationship with the urinary concentration defect and an eventual Li+-induced ciliopathy has to been investigated. Li+-induced NDI has been a matter of investigation since the early 1970s. This manuscript reports the latest clinical and experimental findings in combination with the older fundamental results.

Evaluation of cellular plasticity in the collecting duct during recovery from lithium-induced nephrogenic diabetes insipidus.

Abstract: The cellular morphology of the collecting duct is altered by chronic lithium treatment. We have previously shown that lithium increases the fraction of type-A intercalated cells and lowers the frac...

Double Knockout of the Na+-Driven Cl−/HCO3− Exchanger and Na+/Cl− Cotransporter Induces Hypokalemia and Volume Depletion

Abstract: We recently described a novel thiazide-sensitive electroneutral NaCl transport mechanism resulting from the parallel operation of the Cl-/HCO3- exchanger pendrin and the Na+-driven Cl-/2HCO3- exchanger (NDCBE) in β-intercalated cells of the collecting duct. Although a role for pendrin in maintaining Na+ balance, intravascular volume, and BP is well supported, there is no in vivo evidence for the role of NDCBE in maintaining Na+ balance. Here, we show that deletion of NDCBE in mice caused only subtle perturbations of Na+ homeostasis and provide evidence that the Na+/Cl- cotransporter (NCC) compensated for the inactivation of NDCBE. To unmask the role of NDCBE, we generated Ndcbe/Ncc double-knockout (dKO) mice. On a normal salt diet, dKO and single-knockout mice exhibited similar activation of the renin-angiotensin-aldosterone system, whereas only dKO mice displayed a lower blood K+ concentration. Furthermore, dKO mice displayed upregulation of the epithelial sodium channel (ENaC) and the Ca2+-activated K+ channel BKCa. During NaCl depletion, only dKO mice developed marked intravascular volume contraction, despite dramatically increased renin activity. Notably, the increase in aldosterone levels expected on NaCl depletion was attenuated in dKO mice, and single-knockout and dKO mice had similar blood K+ concentrations under this condition. In conclusion, NDCBE is necessary for maintaining sodium balance and intravascular volume during salt depletion or NCC inactivation in mice. Furthermore, NDCBE has an important role in the prevention of hypokalemia. Because NCC and NDCBE are both thiazide targets, the combined inhibition of NCC and the NDCBE/pendrin system may explain thiazide-induced hypokalemia in some patients.

MicroRNAs: Target Recognition and Regulatory Functions

Abstract: MicroRNAs (miRNAs) are endogenous ∼23 nt RNAs that play important gene-regulatory roles in animals and plants by pairing to the mRNAs of protein-coding genes to direct their posttranscriptional repression. This review outlines the current understanding of miRNA target recognition in animals and discusses the widespread impact of miRNAs on both the expression and evolution of protein-coding genes.

Autophagy in Human Diseases

Abstract: Autophagy in Human Diseases Autophagy is a complex process of intracellular degradation of senescent or malfunctioning organelles. Dysregulated autophagy is associated with certain cancers, neurode...

GSK-3 as potential target for therapeutic intervention in cancer.

Abstract: // James A. McCubrey 1 , Linda S. Steelman 1 , Fred E. Bertrand 2 , Nicole M. Davis 1 , Melissa Sokolosky 1 , Steve L. Abrams 1 , Giuseppe Montalto 3 , Antonino B. D’Assoro 4 , Massimo Libra 5 , Ferdinando Nicoletti 5 , Roberta Maestro 6 , Jorg Basecke 7,8 , Dariusz Rakus 9 , Agnieszka Gizak 9 Zoya Demidenko 10 , Lucio Cocco 11 , Alberto M. Martelli 11 and Melchiorre Cervello 12 1 Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University Greenville, NC, USA 2 Department of Oncology, Brody School of Medicine at East Carolina University Greenville, NC, USA 3 Biomedical Department of Internal Medicine and Specialties, University of Palermo, Palermo, Italy 4 Department of Medical Oncology, Mayo Clinic Cancer Center, Rochester, MN, USA 5 Department of Bio-Medical Sciences, University of Catania, Catania, Italy 6 Experimental Oncology 1, CRO IRCCS, National Cancer Institute, Aviano, Pordenone, Italy. 7 Department of Medicine, University of Gottingen, Gottingen, Germany 8 Sanct-Josef-Hospital Cloppenburg, Department of Hematology and Oncology, Cloppenburg, Germany 9 Department of Animal Molecular Physiology, Institute of Experimental Biology, Wroclaw University, Wroclaw, Poland 10 Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, NY, USA 11 Dipartimento di Scienze Biomediche e Neuromotorie, Universita di Bologna, Bologna, Italy 12 Consiglio Nazionale delle Ricerche, Istituto di Biomedicina e Immunologia Molecolare “Alberto Monroy”, Palermo, Italy Correspondence: James A. McCubrey, email: // Keywords : GSK-3, cancer stem cells, Wnt/beta-catenin, PI3K, Akt, mTOR, Hedgehog, Notch, Targeted Therapy, Therapy Resistance, Mutations, Rapamycin Received : April 24, 2014 Accepted : May 28, 2014 Published : May 28, 2014 Abstract The serine/threonine kinase glycogen synthase kinase-3 (GSK-3) was initially identified and studied in the regulation of glycogen synthesis. GSK-3 functions in a wide range of cellular processes. Aberrant activity of GSK-3 has been implicated in many human pathologies including: bipolar depression, Alzheimer’s disease, Parkinson’s disease, cancer, non-insulin-dependent diabetes mellitus (NIDDM) and others. In some cases, suppression of GSK-3 activity by phosphorylation by Akt and other kinases has been associated with cancer progression. In these cases, GSK-3 has tumor suppressor functions. In other cases, GSK-3 has been associated with tumor progression by stabilizing components of the beta-catenin complex. In these situations, GSK-3 has oncogenic properties. While many inhibitors to GSK-3 have been developed, their use remains controversial because of the ambiguous role of GSK-3 in cancer development. In this review, we will focus on the diverse roles that GSK-3 plays in various human cancers, in particular in solid tumors. Recently, GSK-3 has also been implicated in the generation of cancer stem cells in various cell types. We will also discuss how this pivotal kinase interacts with multiple signaling pathways such as: PI3K/PTEN/Akt/mTORC1, Ras/Raf/MEK/ERK, Wnt/beta-catenin, Hedgehog, Notch and others.