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Sex Differences in Macrophage Polarization During the Early Progression of Renal Disease in Obese Dahl Salt‐Sensitive Rats Prior to Puberty
Author(s) -
Shields Corbin,
Poudel Bibek,
Ekperikpe Ubong,
Brown Andrea,
Smith Stanley,
Cornelius Denise,
Williams Jan
Publication year - 2021
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.2021.35.s1.02057
Subject(s) - medicine , endocrinology , hormone , renal injury , testosterone (patch) , obesity , proteinuria , kidney
Childhood/prepubertal (PPO) obesity has emerged as an epidemic and major health problem over the last few decades and is a risk factor for the development of proteinuria. Recently, we reported that the development of progressive renal injury in obese female and male Dahl salt‐sensitive leptin receptor mutant (SS LepR mutant) rats was associated with increased renal macrophage infiltration as early as 8 weeks of age. The current study investigated whether there are differences in the polarization of infiltrating macrophages in female and male SS LepR mutant rats during the early progression of renal injury (M1; pro‐inflammatory and M2; anti‐inflammatory). Sex hormones were also monitored to determine if the development of renal injury in SS LepR mutant strain occurs prior to puberty. Female and male lean SS and obese SS LepR mutant rats were studied biweekly from 4 to 10 weeks of age monitoring serum sex hormones and renal injury. Estradiol and testosterone levels were similar in all groups at 4 weeks of age and averaged 11±1 and 0.44±0.15 ng/mL, respectively. The levels of estradiol only significantly increased in female SS rats at 10 weeks of age (24±7 ng/mL; p<0.05 vs 4 weeks of age) and remain unchanged in all other groups. When examining the levels of testosterone in male rats, we observed a marked increase in male SS rats only at 10 weeks of age (2.53±0.69 ng/mL; p<0.05 vs 4 weeks of age), and we did not detect any differences from baseline in the other groups. Proteinuria was significantly higher in female and male SS LepR mutant rats as opposed to the values observed in SS rats at 4 weeks of age (56±7 and 60±13 vs 12±4 and 9±3 mg/day, respectively, n=6). While we observed minimal increases in proteinuria in SS rats at 8 weeks of age, proteinuria increased to 288±45 and 376±44 mg/day in female and male SS LepR mutant rats, respectively. We observed no sex differences in proteinuria in either the SS LepR mutant or SS rats. In support of our previous work, renal macrophage (CD68 + ) infiltration was significantly higher in the SS LepR mutant rats when compared to their lean counterparts. Interestingly, the female SS LepR mutant rats displayed significantly higher macrophage (CD68 + ) infiltration than their male counterparts. Moreover, female SS LepR mutant rats displayed significant increases in both macrophage subtypes M1 (CD68 + /iNOS + ) and M2 (CD68 + /CD163 + ) versus male SS LepR mutant rats as well as SS rats. The male SS LepR mutant rats only displayed significant increases in M1 macrophages (CD68 + /iNOS + ) compared to male SS rats. The kidneys from the SS LepR mutant rats displayed significant glomerular injury and marked renal fibrosis versus the values measured in SS rats without any sex differences. These data indicate that the SS LepR mutant strain displays sex differences in renal macrophage polarization and develops renal injury prior to the onset of puberty. The SS LepR mutant strain may be considered a useful model to study the early development of renal injury associated with PPO and to understand the underlying mechanisms that contribute to future risk of obesity‐related CKD.