Ricerca Progetti nazionali, regionali, internazionaliNAZIONALIPRIN 2022Tubular epithelial cell polyploidy

Tubular epithelial cell polyploidy in MYH9-related disease nephropathy

MYH9-related disease (MYH9-RD) is an autosomal-dominant disorder caused by mutations in the MYH9 gene and characterized by different manifestations, including a form of nephropathy that progresses to end-stage kidney disease (ESKD)1-4. The functions of MYH9 in the kidney and the pathogenetic mechanisms of kidney damage of MYH9-RD patients are largely unknown. A recent evidence in mice revealed that genetic inactivation of Myh9 and Myh10 in renal tubular epithelial cells (TEC) results in progressive tubulointerstitial disease, indicating their role in the regulation of TEC functions and suggesting a tubular origin for the MYH9-RD nephropathy5. Interestingly, loss of function of MYH9 resulted in defects in cell division causing an increased generation of polyploid cells in different models6,7. In the kidney, we have described an increased formation of polyploid TEC as an adaptive mechanism to cope with damage, stress, and cell loss8. As in the liver9,10, and in the heart10,11, also in the kidney this mechanism is associated with long-term trade-offs, namely fibrosis and senescence, contributing to chronic kidney disease (CKD), and its inhibition is able to halt CKD progression [De Chiara L, first round of peer review in Nat Commun]. This background motivated us to study the role of MYH9 in TEC polyploidization, aiming to explain with this mechanism the progression to ESKD of MYH9-RD patients. Since the risk of developing nephropathy and its severity depend on the specific MYH9 mutation, the project aims also to further study the effects of these variants in TEC polyploidization and in determining specific features of the kidney phenotype in individual patients with different MYH9 genotypes. To this aim, we will use a personalised approach based on urine-derived renal progenitor cells (u-RPC) isolated from MYH9-RD patients. In summary, this proposal aims to: 1. uncover the role of MYH9 in TEC polyploidization identifying this mechanism as a crucial trigger of CKD and ESKD progression, and as a new druggable target; 2. define the role of specific MYH9 mutations in determining TEC polyploidization and specific features of the renal phenotype in individual MYH9-RD patients, by developing a personalised tool for modeling the MYH9-RD nephropathy. This is of particular clinical importance to predict the development and severity of renal impairment in those patients with a variable evolution of kidney disease; 3. uncover pathways controlling TEC polyploidization to find new druggable targets for preventing CKD and ESKD in MYH9-RD patients. We expect that the results of this proposal will elucidate the pathogenesis of MYH9-RD nephropathy and the risk of ESKD progression, identifying a key role of TEC polyploidization in this context. Moreover, we aim to provide patients with MYH9-RD with new therapeutic approaches to reduce the risk of progression to kidney failure, decreasing the disease impact on patient's quality of life.

 

Data di avvio 18 Ottobre 2023

Data di completamento 18 Ottobre 2025

Total cost  € 185200,00

 

Progetto 2022X725LA finanziato all’interno del Bando PRIN 2022 di cui al Decreto Direttoriale n. 104 del 02/02/2022 nell’ambito del Piano Nazionale di Ripresa e Resilienza, Missione 4 – Componente 2. Dalla Ricerca all’Impresa - Investimento 1.1 Fondo per il Programma Nazionale della Ricerca (PNR) e Progetti di Ricerca di Rilevante Interesse Nazionale (PRIN), finanziato dall’Unione europea – NextGenerationEU – CUP B53D23021970006