Nuclear receptors in podocytes as new targets in the kidney failure associated with obesity and typwe 2 diabetes
Spain (IFMSA-SPAIN)-University of Rey Juan Carlos, Madrid
Basic sciences of health
Carlos Goicoechea
Gema Medina-Gomez
English, Spanish
8 weeks
Cities/Months Jan Feb Mar Apr May Jun Jul Augt Sep Oct Nov Dec
No No No No No Yes Yes No No No No No
Type of Research Project
- Basic science
What is the background of the project?
The Metabolic Syndrome (MetS), characterized by the clustering in the same individual of obesity, insulin resistance (IR), Type 2 diabetes (T2D) and hypertension, is increasing due to the increased prevalence of obesity. Certainly still unappreciated the associated risk of developing chronic kidney failure in individuals with MetS is also increasing at fast pace. Elucidating the factors that prime this evolution or conversely identifying factors that may prevent/delay the natural history of kidney disease is of paramount importance. It is known that positive energy balance leads to obesity, which is associated with the development of lipotoxicity, a state produced by the accumulation of excessive reactive lipid species in metabolically relevant organs. Nuclear receptors (NRs) are ligand-dependent transcription factors, which can activate or suppress the transcription of target genes in lipid metabolism and inflammation in response to their specific agonists. RXRs are ligand-dependent nuclear receptors that play an important role as a heterodimeric partner for other NR. Numerous studies have reported the broad impact of RXR ligands on metabolic regulation; however their role in kidney failure is unknown. We propose the novel hypothesis that obesity-associated lipotoxicity is an important pathogenic factor for T2D-associated kidney failure.
What is the aim of the project?
We aim to identify RXR-controlled mechanisms in podocyte gene regulation and whether podocyte RXRs can be targets in T2D-associated kidney failure. We will develop our work in three specific aims: In specific aim 1 we will identify and characterize novel molecular mechanisms involved in lipotoxicity-induced podocyte failure in obesity and T2D and we will define the role of RXR in these processes. In specific aim 2 we will identify RXR signaling pathways involved in the lipotoxicityinduced podocyte failure by using a non-biased Systems Biology approach. And in specific aim 3 we will develop an hypothesis-driven renal failure biomarkers analysis in obese human samples.
What techniques and methods are used?
For this study, we will use genetically modified podocyte cell-specific knockout mouse model and podocyte cell line to elucidate the functional impact of podocyte RXR (RXRα and RXRβ) expression in the development of kidney failure. We will use state of the art purposely designed methodology including a research strategy approach based on omics technologies (lipidomics, metabolomics and transcriptomics).
What is the role of the student?
- The student will observe the practical experiments but will be highly involved in the analysis of the results
What are the tasks expected to be accomplished by the student?
We will use genetic and pharmacological manipulations to dissect the functions of RXRs and their target genes in the kidney of mouse model of obesity and diabetes. The specific tasks that the student will take part on will be: 1. We will determine the contribution of RXRs with the use of an animal model, which is lacking the podocyte expression of RXRα and RXRβ (podRXR-KO mouse). We have generated this mouse. In order to exacerbate podocyte damage with lipids excess, mice will be challenged with high fat diet (HFD) since weaning until body weight curves separate from the ones on chow diet. The student will help with the weights of the groups of animals and food intake measurements every week. Also pressure measurements will be done in the different groups of animals. The student will observe other in vivo specialized technics (Glucose and Insulin tolerant test) Tasks that he/she has to perform done under supervision (always with qualified personnel due to animal work in animal facility)) 2. Podocyte RXRα/β KO cell line will be obtained using podocytes from podRXRKO mouse in vitro. Culture of podocytes will be performed by lab technicians in the groups, but the student will help to culture the podocytes and to do the specific pharmacological treatments (work that has to be done under supervision). Specific techniques as routine (immunostaining with different antibodies, RT-PCR) to characterize the cell line will be perform by the student, tasks that he/she has to perform on his/her own after specific training.
Will there be any theoretical teaching provided (preliminary readings, lectures, courses, seminars etc)
Preliminary readings from already published works from the group to understand better the project and specific reading and training in the technics that he/shewill be used with the pocodyte cultures.
What is expected from the student at the end of the research exchange? What will be the general outcome of the student?
- The student will prepare a poster
- The student will prepare an abstract
- The student’s name will be mentioned in a future publication
What skills are required of the student? Is there any special knowledge or a certain level of studies needed?
Subjects passed: Biochemistry and molecular biology, physiology
Are there any legal limitations in the student’s involvement
Type of students accepted
This project accepts:
- Medical students
- Graduated students (less than 6 months)
- Students in biomedical fields
- Lipotoxicity as a trigger factor of renal disease. Izquierdo-Lahuerta A; Martínez-García C; Medina-Gómez G. J Nephrol. 2016 Oct;29(5):603-10. doi: 10.1007/s40620-016-0278-5.
- Renal Lipotoxicity-Associated Inflammation and Insulin Resistance Affects Actin Cytoskeleton Organization in Podocytes. Martínez-García C; Izquierdo-Lahuerta A; Vivas Y; Velasco I; Yeo TK; Chen S; Medina-Gomez G. PLoS One. 2015 Nov 6;10(11):e0142291.
- Accelerated renal disease is associated with the development of metabolic syndrome in a glucolipotoxic mouse model. Martínez-García C; Izquierdo A; Velagapudi V; Vivas Y; Velasco I; Campbell M; Burling K; Cava F; Ros M; Oresic M; Vidal-Puig A; Medina-Gomez G. Dis Model Mech. 2012 Sep;5(5):636-48.