Neutralizing MIP3 Reduces Renal Immune Cell Infiltration and Progressive Renal Injury in Young Obese Dahl Salt-Sensitive Rats

Overview

Journal J Pharmacol Exp Ther

Specialty Pharmacology

Date 2022 Dec 12

PMID 36507846

Authors

Ubong S Ekperikpe

Bibek Poudel

Corbin A Shields

Sautan Mandal

Denise C Cornelius

Jan M Williams

Affiliations

Soon will be listed here.

Abstract

Recently, we reported that the early progression of renal injury in obese Dahl salt-sensitive leptin receptor mutant (SSmutant) rats was associated with increased macrophage inflammatory protein 3- (MIP3) expression prior to puberty. Therefore, this study tested the hypothesis that MIP3 plays a role in recruiting immune cells, thereby triggering renal inflammation and early progressive renal injury in SSmutant rats prior to puberty. Four-week-old Dahl salt-sensitive (SS) and SSmutant rats either served as control (IgG; intraperitoneal, every other day) or received MIP3-neutralizing antibody (MNA; 100 µg/kg) for 4 weeks. MNA reduced circulating and renal MIP3 levels and proinflammatory immune cells by 50%. Although MNA treatment did not affect blood glucose and plasma cholesterol levels, MNA markedly decreased insulin resistance and triglyceride levels in SSmutant rats. We observed no differences in mean arterial pressure (MAP) between SS and SSmutant rats, and MNA had no effect on MAP in either strain. Proteinuria was significantly increased in SSmutant rats versus SS rats over the course of the study. Treatment with MNA markedly decreased proteinuria in SSmutant rats while not affecting SS rats. Also, MNA decreased glomerular and tubular injury and renal fibrosis in SSmutant rats while not affecting SS rats. Overall, these data indicate that MIP3 plays an important role in renal inflammation during the early progression of renal injury in obese SSmutant rats prior to puberty. These data also suggest that MIP3 may be a novel therapeutic target to inhibit insulin resistance and prevent progressive proteinuria in obese children. SIGNIFICANCE STATEMENT: Childhood obesity is increasing at an alarming rate and is now being associated with renal disease. Although most studies have focused on the mechanisms of renal injury associated with adult obesity, few studies have examined the mechanisms of renal injury involved during childhood obesity. In the current study, we observed that the progression of renal injury in obese Dahl salt-sensitive leptin receptor mutant rats was associated with an increase in MIP3, a chemokine, before puberty, and inhibition of MIP3 markedly reduced renal injury.

Citing Articles

Metformin reduces insulin resistance and attenuates progressive renal injury in prepubertal obese Dahl salt-sensitive rats.

Ekperikpe U, Mandal S, Holt S, Daniels J, Johnson T, Cooper J Am J Physiol Renal Physiol. 2023; 325(3):F363-F376.

PMID: 37498548 PMC: 10639024. DOI: 10.1152/ajprenal.00078.2023.

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