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The Early Progression of Renal Injury in Obese Dahl Salt‐Sensitive Rats is Associated with Increased M2 Macrophage Infiltration

Previously, we reported that, prior to puberty, the obese Dahl salt‐sensitive leptin receptor mutant (SSLepRmutant) strain displays proteinuria and renal injury independent of hyperglycemia and elevations in arterial pressure. Recently, we observed that the early development of renal injury in the obese SSLepRmutant strain was associated with a 5‐fold increase in renal infiltration of macrophages compared to SSWT rats. In this study, we examined whether depletion of macrophages with clodronate would reduce renal injury in prepubescent obese SSLepRmutant rats. Four week‐old SSWT and SSLepRmutant rats were separated into four groups (n=8/group): (1) SSWT and (2) SSLepRmutant rats treated with vehicle and (3) SSWT and (4) SSLepRmutant rats treated with clodronate (50 mg/kg, i.p., twice/week) for 4 weeks. While administration of clodronate did not alter the macrophage population in SSWT rats, clodronate reduced macrophages in the kidneys from SSLepRmutant rats compared to vehicle‐treated rats (8±4 vs. 33±10 % gated, respectively; p<0.05 vs. vehicle) without altering the monocyte population. Interestingly, we did not observe any effects on MAP in animals chronically treated with clodronate. At baseline, protein excretion was significantly higher in SSLepRmutant rats compared to SSWT rats (70±14 vs. 10±3 mg/day, respectively; p<0.05 vs. SSWT) that further increased over the course of the study (335±82 vs. 45±14 mg/day, respectively; p<0.05 vs. SSWT). After 2 weeks of treatment with clodronate, protein excretion was markedly reduced in the SSLepRmutant strain (159±32 vs. 303±52 mg/day; p<0.05 vs. vehicle). However, after 4 weeks of treatment, the effect of clodronate was no longer observed in the SSLepRmutant strain (346±195 vs. 399±50 mg/day). Chronic treatment with clodronate significantly decreased glomerular injury and renal fibrosis in the obese SSLepRmutant strain. Since clodronate depletes all macrophages: M1 (pro‐inflammatory) and M2 (anti‐inflammatory or pro‐inflammatory), we also examined macrophage polarization in the vehicle treated lean SSWT and obese SSLepRmutant strain prior to puberty at 8 weeks of age. We found that the M1/M2 ratio was significantly higher in the lean SSWT versus obese SSLepRmutant rats (1.60±0.05 vs. 0.54±10, respectively; p<0.05 vs. SSWT), demonstrating more M2 macrophages in the kidneys of the obese SSLepRmutant strain. Overall, these data show that the early development of renal injury in the obese SSLepRmutant strain is associated with increased renal M2 macrophages and suggests that M2 macrophages may be a therapeutic target in obesity‐induced renal injury.