Role of macrophage inflammatory protein 3-alpha and dendritic cells during obesity-induced renal disease
Description: Childhood obesity is currently an epidemic. Increasingly, markers of renal injury such as microalbuminuria and high serum creatinine are seen in children and adolescents with obesity. Interestingly, renal injury in obese children occurs independent of diabetes or hypertension. Therefore, there is a need to study mechanisms of renal injury in this population. Few studies have investigated mechanisms of renal injury in obese children due to the lack of a suitable model to recapitulate features of renal injury in this unique population. Recently, we reported that the Dahl salt-sensitive leptin receptor mutant rat (obese rat) develops renal injury without hyperglycemia or elevations in mean arterial pressure (MAP), before puberty. Therefore, this is an ideal and translational model to study mechanisms of obesity-induced renal disease (OIRD) in children. Studies from our laboratory have observed that the development of renal injury in obese rats is associated with insulin resistance, renal hyperfiltration, and the increased renal expression of macrophage inflammatory protein 3-alpha (MIP3a; inflammatory cytokine that is strongly chemotactic for lymphocytes and dendritic cells). The aim of this project is to study the role of insulin resistance-mediated hyperfiltration on glomerular injury, renal MIP3a expression, renal inflammation, and progressive renal injury in obese rats. Aim 1 of this proposal will investigate the role of insulin resistance-mediated renal hyperfiltration in glomerular and tubular injury and renal inflammation in obese rats. Four-week obese rats and their lean salt-sensitive (SS) counterparts will be administered metformin (300 mg/kg ip) daily for four weeks, while markers of glomerular hyperfiltration, glomerular injury, renal inflammation, renal fibrosis, renal oxidative stress, and progressive renal injury and markers of systemic insulin resistance and dyslipidemia will be measured. Isolated glomeruli experiments will also be performed to study the effects of stretch on the glomerular secretion of MIP3a and ROS. Aim 2 of the proposal will investigate the role of MIP3a on renal dendritic cell (DC) and T-cell infiltration and activation in progressive OIRD. This will be investigated with two aims. Sub-aim 1 will determine the role of MIP3a in the recruitment of renal DCs and T-cells in OIRD. Four-week-old obese rats and their lean SS counterparts will be administered a MIP3a neutralizing antibody (100 mcg/kg ip) every alternate day
Funder: American Heart Association
Amount: $65,110
Funding type: training
Funder scheme: Predoctoral Fellowship
Start date: 2023-01-01
End date: 2024-01-16
Investigators: Ubong Ekperikpe, Ubong Ekperikpe
Institution: University of Mississippi Medical Center
Subfield: Nephrology
Field: Medicine
Domain: Health Sciences
Funded outputs count: 5
Funder award ID: 23PRE1025798
OpenAlex ID: G6734795352