Impact of Obesity on Renal Structure and Function in The Absence of Hypertension: Evidence From Melanocortin‐4 Receptor (MC4R) Deficient Mice

Abstract

The purpose of this study was to test if long-term obesity and its related metabolic abnormalities would cause renal injury in the absence of hypertension. Markers of renal injury and salt-sensitivity of blood pressure that normally occur with renal injury were assessed in 52 week obese MC4R (−/−) and lean C57BL/6J wild type (WT) mice (n=5–6). Mean arterial pressure (MAP) was monitored by telemetry during 3 days of normal salt diet (NSD-0.4% NaCl) and 12 days of high salt diet (HSD-4% NaCl). MC4R (−/ −) mice were 60% heavier but had similar ΔMAP as WT mice (115 ± 2 and 115 ± 1 mmHg) on NSD. Increases in MAP with HSD were not significantly different between groups (average MAP- MC4R (−/ −) 5 ± 2; WT 2 ± 1 mmHg). Glomerular tuft area was 23 % greater in MC4R (−/ −) than WT mice but Bowman's space, total glomerular area and mesangial matrix accumulation were not different between groups. Renal TGF-β mRNA expression was 4-fold greater in MC4R (−/ −) than WT mice. Urinary albumin excretion was similar between groups (MC4R (−/ −) 32 ± 11 vs WT 26 ± 3 μg/24hr). MC4R (−/−) were hyperinsulinemic, hyperleptinemic and euglycemic compared with WT mice. In summary, despite long-term obesity, 52-week normotensive MC4R (−/−) mice have no evidence of major renal injury and are only slightly salt-sensitive, although they have glomerulomegaly and increased renal TGF-β gene expression. These data suggest that obesity and its related metabolic abnormalities per se may not cause major renal injury in the absence of hypertension. Whether obesity potentiates hypertension induced renal injury remains to be investigated. (NHLBI grant PO1 Hl51971).