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Smoking Effects on the Renal and Cardiac Phenotypes in Cystic Mice due to Pkd1 Inactivation

Grant number: 15/17152-3
Support type:Regular Research Grants
Duration: November 01, 2016 - October 31, 2018
Field of knowledge:Health Sciences - Medicine - Medical Clinics
Principal Investigator:Luiz Fernando Onuchic
Grantee:Luiz Fernando Onuchic
Home Institution: Faculdade de Medicina (FM). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common human inherited diseases, presenting an estimated prevalence of 1/400-1000. This disorder is caused by mutation in one of two genes: PKD1 (Polycystic Kidney Disease 1) or PKD2. Most of the cases (85%) occur due to mutations in PKD1, while PKD2 mutations respond for 15% of them. ADPKD usually manifests in adulthood and is characterized by bilateral development of multiple renal cysts. Approximately half of the patients evolve to end-stage renal disease prior to reaching the end of the sixth decade of life. According to the knudsonian two-hit model proposed for cyst formation in ADPKD, the germline mutation constitutes the first hit while a somatic mutation in the previously normal allele represents the second event. Studies carried out in recent years, however, suggest the need for a third hit for the rapid and broad cyst development in mature mouse kidneys, an observation not verified in developing kidneys. It must be noted that the renal ischemia/reperfusion (IR) insult can behave as this additional hit. Among the extrarenal phenotypes associated with ADPKD, which characterize its systemic nature, the cardiovascular one stands out, including systemic hypertension and cardiomyopathy. Smoking affects deleteriously renal function, particularly in the elderly, and the cardiovascular phenotype. Cigarette smoke contains not only several toxic substances, many of them carcinogenic, but also nicotine, which is associated with increased risk of progression to chronic kidney insufficiency in nephropaths. Smoking can also favor renal function deterioration in men with ADPKD. Among the cellular properties of polycystin-1, the PKD1 gene product, reduction in cell proliferation and apoptosis stand out, as well as its pro-cell differentiation effect. In addition, the ADPKD renal disease is associated with oxidative stress, inflammation and fibrosis. Substances present in the cigarette, in turn, display potentially mutagenic, proliferative, inflammatory, redox disbalance-inducing, anti-apoptotic and hemodynamic adverse effects on the kidney, the last possibly capable of limiting blood flow to specific areas of the organ. In this scenario, it is unknown whether the smoking adverse effects on ADPKD progression are due to specific actions in this disease or to actions common to the progression of the several nephropathies. It is also not known whether smoking affects this illness cardiac phenotype. To answer these questions, we will use a cystic animal model orthologous and phenotypically similar to human ADPKD, the Pkd1cond/cond:Nestincre mouse, exposing it to smoking since its conception. The tobacco effects on disease progression will be evaluated at the age of 16-18 weeks, comparing these mice with control non-smoking cystic animals. Such analyses will include: 1) biochemical determinations directed to renal functional evaluation; 2) quantification of renal and cyst volume; 3) cardiac functional analysis; 4) evaluation of apoptosis, inflammation and fibrosis in kidney and heart tissue; 5) analysis of renal cell proliferation and redox metabolism; and 6) evaluation of animal survival. (AU)

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 JAN 14 2020. Web of Science Citations: 0.

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