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Evaluation of fibrosis factors and microRNAs in the progression of the polycystic renal disease in a PKD1 deficient murine model

Grant number: 18/09135-0
Support Opportunities:Scholarships in Brazil - Post-Doctoral
Effective date (Start): June 01, 2018
Effective date (End): August 31, 2022
Field of knowledge:Health Sciences - Medicine - Medical Clinics
Principal Investigator:Ita Pfeferman Heilberg
Grantee:Juan José Augusto Moyano Muñoz
Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil
Associated research grant:15/23345-9 - MicroRNAs, extracellular vesicles and stem cells: physiology, pathophysiological role and therapeutic potential in renal diseases, AP.TEM


Autosomal Dominant Polycystic Kidney Disease (ADPKD), the most common monogenic renal disease, is responsible for 4.4 - 10% of hemodialysis patients. The clinical manifestations appear over the 5th decade of life and most patients undergo end-stage renal disease around 60 years old. This disease is characterized by multiple cysts formation and growth, resulting in progressive cyst expansion and consequently destruction of renal architecture. Extra-renal manifestations such as hepatic cysts, valvular heart disease and hypertension are common. The renal cysts are lined by a monoclonal epithelial cell layer characterized by high proliferative and apoptosis rates, set in an interstitial inflammatory environment and fibrosis process. This interstitial fibrosis is associated with loss of renal function in ADPKD and some studies suggest that the key mediator of glomerular and tubular fibrosis, in several chronic kidney diseases (CKDs), could be TGF-² (transforming growth factor ²), partly through induction of epithelial-mesenchymal transition (EMT). This process is characterized by the dedifferentiation of cells with loss of epithelial and acquisition of mesenchymal features, and associating myofibroblasts molecules. The cyst expansion leads to tubular cells stretching, consequently initiating TGF-² production and leading to EMT, collagen production and fibrosis. Some evidences showed association of microRNAs expression with the TGF-² pathway in renal diseases, including ADPKD. In general, TGF-beta seems to regulate several pro-fibrotic and pro-inflammatory microRNAs, protecting the kidney mainly through EMT inhibition and extracellular deposition suppression. In this scenario, the differential renal expression of mRNAS and microRNAs involved on EMT process and fibrosis, in ADPKD, needs to be evaluated. The employment of Pkd1cond/cond:Nestincre mice, an orthologous murine model for ADPKD, in the current project, aimsto evaluate the differential expression of genes related to fibrosis, such as TGF-², regulated and potentially regulators miRNAs of such genes, in different stages of the polycystic renal disease, The comprehension of the underlying mechanisms of the fibrosis process in ADPKD is very important for futures attempts of halting the progression of the disease.

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Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
MUNOZ, J. J.; ANAUATE, A. C.; AMARAL, A. G.; FERREIRA, F. M.; MECA, R.; ORMANJI, M. S.; BOIM, M. A.; ONUCHIC, L. F.; HEILBERG, I. P.. Identification of housekeeping genes for microRNA expression analysis in kidney tissues of Pkd1 deficient mouse models. SCIENTIFIC REPORTS, v. 10, n. 1, . (15/17152-3, 11/21593-4, 18/09135-0, 15/23345-9)
MUNOZ, JUAN J.; ANAUATE, ANA C.; AMARAL, ANDRESSA G.; FERREIRA, FREDERICO M.; WATANABE, ELIESER H.; MECA, RENATA; ORMANJI, MILENE S.; BOIM, MIRIAN A.; ONUCHIC, LUIZ F.; HEILBERG, ITA P.. Ppia is the most stable housekeeping gene for qRT-PCR normalization in kidneys of three Pkd1-deficient mouse models. SCIENTIFIC REPORTS, v. 11, n. 1, . (15/17152-3, 11/21593-4, 18/09135-0, 15/23345-9)

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