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Depletion of macrophages with clodronate partially reduces the progression renal injury in obese Dahl salt‐sensitive rats during prepubertal obesity
Author(s) -
Poudel Bibek,
Shields Corbin A.,
Pennington Alyssa,
Cornelius Denise C.,
Williams Jan M.
Publication year - 2019
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2019.33.1_supplement.573.5
Subject(s) - endocrinology , medicine , renal injury , proteinuria , excretion , obesity , leptin , mutant , leptin receptor , population , kidney , chemistry , gene , biochemistry , environmental health
Prepubertal obesity (PPO) is now considered a risk factor for the development of proteinuria and renal injury in children. Recently, we reported that, prior to puberty, Dahl salt‐sensitive leptin receptor mutant (SS LepR mutant) rats display proteinuria and renal injury as early as 6 weeks of age independent of hyperglycemia and elevations in arterial pressure. Moreover, the early development of renal injury was associated with an increase in the renal infiltration of macrophages in the SS LepR mutant strain compared to their lean SS WT counterparts (39±14 vs. 11±3 % gated, respectively; p<0.05 vs. SS WT ). Therefore, the current study examined whether depletion of macrophages with clodronate would reduce renal injury in the SS LepR mutant strain during PPO. Four week‐old SS WT and SS LepR mutant rats were separated into four groups (n=4/group): (1) SS WT and (2) SS LepR mutant rats treated with vehicle‐PBS and (3) SS WT and (4) SS LepR mutant rats treated with clodronate (50 mg/kg, i.p., twice/week) for 4 weeks. While administration of clodronate did not have an effect in SS WT rats, clodronate significantly depleted macrophages in the kidneys of SS LepR mutant rats compared to vehicle‐treated rats without altering the monocyte population (8±4 versus 33±10 % gated, respectively; p<0.05 vs. vehicle). At baseline, protein excretion was significantly higher in SS LepR mutant rats compared to SS WT rats (70±14 vs. 10±3 mg/day, respectively; p<0.05 vs. SS WT ) that further increased over the course of the study (335±82 vs. 45±14 mg/day, respectively; p<0.05 vs. SS WT ). Clodronate had no effect on the progression of proteinuria or renal histopathology in SS WT rats. After 2 weeks of treatment with clodronate, protein excretion was markedly reduced in the SS LepR mutant strain (86±36 vs. 200±35 mg/day; p<0.05 vs. vehicle). However, after 4 weeks of treatment, the effect of clodronate was no longer observed in the SS LepR mutant strain (270±90 vs. 335±82 mg/day). The kidneys from SS LepR mutant rats displayed glomerular injury with increased mesangial expansion and renal fibrosis versus SS WT rats. Interestingly, treatment with clodronate had no effect on glomerular injury but significantly decreased renal fibrosis in the SS LepR mutant strain compared to their vehicle‐treated obese counterparts. Overall, these data indicate that the early development of renal injury in the SS LepR mutant strain is associated with macrophage infiltration, which can be blunted by chronic macrophage depletion. Support or Funding Information This study was supported by GM104357 and DK109133. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .