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Mezzabotta, Federica (2009) Nefrocalcinosi e placche di Randall: un processo di biomineralizzazione a livello renale? Studio cellulare e molecolare di un processo di calcificazione spontanea di cellule papillari in vitro. [Tesi di dottorato]

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Abstract (inglese)

The pathogenesis of calcium-oxalate (CaOx) renal stones is still debated. Randall’s plaque may represent an ideal site on which overgrowths of CaOx or calcium phosphate could grow into stones. The presence of hydroxyapatite (a mineral, chemically similar to the mineral component of bones) in these structures suggests that a process of biomineralization is in progress.
Studies on vascular calcifications demonstrate that cells of mesenchymal origin (pericytes, calcifying vascular cells, vascular smooth muscle cells) may differentiate in osteoblast-like cells determining the synthesis of typical bone osteoid proteins (osteopontin, osteocalcin, osteonectin) in a biomineralization process similar to osteogenesis. Since these premises, we hypothesize that cells located in the papilla may differentiate toward the osteogenic lineage, determining the synthesis of typical bone osteoid proteins and hydroxyapatite mineralization of renal tissue. If this phenomenon indeed happens, it might well occur in renal diseases associated with nephrocalcinosis. Among these, the medullary sponge kidney (MSK) disease is frequently associated with calcium oxalate nephrolithiasis and nephrocalcinosis. Our research group found that GDNF (glial derived neurotrophic factor) mutations could be related to MSK in a subgroup of patients with nephrolithiasis and bilateral MSK.
Papillary primary cells have been obtained from a surgical biopsy of the site remote from cancer in a patient with familiar MSK and with a GDNF eterozygous mutation.
Analysis of the biopsy by Von Kossa staining and ESEM (Environmental Scanning Electron Microscope) analysis evidenced papillary nephrocalcinosis and a small calcium-phosphate plaque.
We observed the spontaneous tendency of cells, starting from p2, to overlap and aggregate to form nodules with a behaviour similar to that described for calcifying pericytes in culture. The cellular phenotyping performed by immunocytochemistry (ICH) with marker for von Willebrand factor, ?SMA, cytokeratin, E-caderin, ZO-1, vimentin, desmin and 3G5 (pericyte marker) evidenced heterogeneity at first passages; however starting from p2, cells were mainly positive for mesenchymal markers.
Calcium phosphate deposits were detected by Von Kossa staining, SEM (Scanning Electron Microscope) analysis starting from p3; positive alkaline phosphatase cells were also detected.
By ICH analysis cells and nodules were osteocalcin and osteonectin positive and osteopontin negative. These results were confirmed by the RT PCR studies. Expression levels of Cbfa1 (a transcriptor factor regulating osteoblast specific genes) and osteonectin increased in cells starting from p1 to p4, paralleling the development of nodules. Instead, the expression levels of osteopontin decreased during the same passages.
Primary cultures of renal papillary cells from a patient matched for age and gender but without MSK or nephrolithiasis, were used as control. Cells were incubated with glycerophosphate and dexametazone to induce an osteogenic phenotype, but not spontaneous neither induced nodular growth was observed.
The study of GDNF expression revealed that this gene was down-regulated in MSK cells, suggesting its involvement in the observed phenomenon.
Our data indicate that a spontaneous process of calcification was active in MSK cells, suggesting that in the renal papilla may be present cells that can undergo osteogenic differentiation.
Whether this process was related to the transdifferentiation of resident renal cells or to the osteogenic differentiation of renal progenitors has to be clarified.
The presence of GDNF mutation may have a role in the osteogenic differentiation, conferring some degree of immaturity to papillary cells, thereby predisposing them to transdifferentiation.
Our results suggest a new pathogenetic mechanism for nephrocalcinosis in MSK and possibly in other neprholithiasis.


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Abstract (italiano)

La patogenesi della calcolosi renale ossalico-calcica è oggetto di discussione.
Le placche di Randall originano nella membrana basale dell’ansa di Henle e agiscono come siti di ancoraggio per la formazione di calcoli. La presenza di idrossiapatite (chimicamente simile alla componente minerale dell’osso) in queste strutture potrebbe deporre per un processo di biomineralizzazione attiva.
Studi sulle calcificazioni vascolari hanno dimostrato che cellule di origine mesenchimale (periciti, cellule vascolari calcificanti, cellule vascolari muscolari lisce) possono differenziare in cellule con fenotipo osteoblastico, con conseguente sintesi di proteine tipiche dell’osteoide (osteopontina, osteocalcina, osteonectina) in un processo di biomineralizzazione simile all’osteogenesi.
Con queste premesse si ipotizza che cellule della papilla possano differenziare verso la linea osteogenica, determinando la sintesi di proteine tipiche dell’osso e mineralizzazione in apatite del tessuto renale. Questo fenomeno potrebbe aver luogo in patologie renali associate a nefrocalcinosi, come il rene con midollare a spugna (MSK).
Recentemente il nostro gruppo di ricerca ha trovato che in alcuni pazienti con nefrolitiasi e MSK bilaterale sono presenti mutazioni del gene GDNF (glial derived neurotrophic factor), che potrebbero essere correlate con la malattia.
Da biopsia chirurgica da polo indenne per carcinoma renale in una paziente con MSK e portatrice di una mutazione in eterozigosi di GDNF sono state allestite colture primarie di cellule papillari renali.
L’analisi della biopsia renale ha evidenziato nefrocalcinosi papillare e una piccola placca di fosfato di calcio.
Abbiamo osservato la crescita spontanea in vitro delle cellule fino al passaggio p4, notando nelle cellule la capacità di organizzarsi in noduli, a partire dal passaggio p2, con una modalità simile a quella descritta per i periciti calcificanti. E’ stata condotta un’analisi immunocitochimica (ICH) per tipizzare i vari tipi cellulari con marcatori per cellule endoteliali (von Willebrand), cellule muscolari lisce (?SMA), cellule epiteliali (citocheratina, E-caderina, ZO-1), cellule mesenchimali (vimentina e desmina) e periciti (3G5). L’analisi ha evidenziato eterogeneità cellulare al p1 e, a partire dal p2, la comparsa di un fenotipo mesenchimale.
La presenza di depositi di fosfato di calcio nelle cellule e/o nei noduli è stata rivelata mediante colorazione con il reagente di Von Kossa e analisi al microscopio elettronico a scansione (SEM); il saggio della fosfatasi alcalina ha evidenziato alcune cellule positive nelle vicinanze dei noduli.
Lo studio ICH dei marcatori osteogenici ha rivelato una positività per osteocalcina e osteonectina e una negatività per osteopontina nelle cellule e nei noduli.
Questi risultati sono stati confermati attraverso studi di RT PCR nei quali i livelli di espressione di osteonectina e di Cbfa1 (fattore trascrizionale regolatore dell’espressione dei geni osteogenici) aumentavano a partire dal p1 fino al p4, in parallelo allo sviluppo dei noduli; al contrario i livelli di osteopontina diminuivano durante gli stessi passaggi.
Lo studio dei livelli di espressione di GDNF nelle cellule MSK ha mostrato una down-regolazione del gene, suggerendo un suo possibile coinvolgimento nel fenomeno osservato.
Sono state allestite come controllo colture primarie di cellule renali papillari provenienti da un soggetto di sesso ed età comparabili, senza MSK né nefrolitiasi. Le cellule al passaggio p3 sono state incubate con glicerolfosfato e dexametazone per la possibile induzione di un fenotipo osteogenico ma non hanno presentato crescita nodulare né spontanea né indotta.
I dati raccolti depongono un processo attivo e spontaneo di calcificazione nelle cellule MSK in coltura, suggerendo che nella papilla renale sono presenti cellule in grado di differenziare verso la linea osteoblastica.
Se questo processo sia dovuto al transdifferenziamento di cellule renali residenti o al differenziamento di progenitori renali verso il lineaggio osteogenico non è ancora noto e dovrà essere approfondito.
La presenza della mutazione di GDNF potrebbe svolgere un ruolo nella differenziazione osteogenica, conferendo alle cellule un’immaturità che potrebbe renderle maggiormente suscettibili ad un possibile fenomeno di transdifferenziamento.
I nostri risultati suggeriscono un nuovo meccanismo patogenetico per la nefrocalcinosi in MSK e probabilmente anche in altre nefrolitiasi.


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Tipo di EPrint:Tesi di dottorato
Relatore:Anglani, Franca
Correlatore:Ceol, Monica
Dottorato (corsi e scuole):Ciclo 21 > Scuole per il 21simo ciclo > SCIENZE MEDICHE, CLINICHE E SPERIMENTALI > SCIENZE NEFROLOGICHE
Data di deposito della tesi:30 Gennaio 2009
Anno di Pubblicazione:Gennaio 2009
Parole chiave (italiano / inglese):NEFROCALCINOSI, TRANSDIFFERENZIAMENTO
Settori scientifico-disciplinari MIUR:Area 06 - Scienze mediche > MED/14 Nefrologia
Struttura di riferimento:Dipartimenti > Dipartimento di Scienze Mediche e Chirurgiche
Codice ID:1780
Depositato il:30 Gen 2009
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