Sex Differences in Distal Tubular Injury and Renal Inflammation in Intrauterine Growth‐ Restricted Offspring After Uni‐nephrectomy in Late Adulthood

Abstract

Low birth weight (LBW) and aging are well‐established risk factors for kidney disease, but little is known about the compounded effect of aging in LBW individuals. Our laboratory uses a model of intrauterine growth restriction (IUGR) induced by placental insufficiency in the rat to study the association between LBW and chronic disease. We previously reported that male IUGR offspring have elevated blood pressure (BP) at 3 months of age, while female IUGR are protected from increased BP until 12 months of age. Whether sex alters the risk of renal disease in LBW individuals is unknown. Although hypertension does not completely account for the increased risk of kidney disease in LBW individuals, it is a likely contributor. Therefore, we hypothesize that male IUGR offspring will exhibit greater evidence of kidney injury compared to female IUGR due to the longer exposure to high BP. We tested the hypothesis that male IUGR offspring are programmed for enhanced susceptibility to a chronic renal insult during late adulthood while female IUGR offspring remain protected. At 18 months of age, rats underwent uni‐nephrectomy (Uni‐X) or a sham procedure (Sham). After one month, glomerular filtration rate (GFR) was measured by FITC‐sinistrin clearance, urinary markers of renal injury and expression of renal inflammatory markers were quantified, and histological injury was scored by two blinded observers. Male offspring (control Sham, IUGR Sham, control Uni‐X, and IUGR Uni‐X) had greater renal mass determined by kidney weight and kidney surface area, increased renal injury determined by proteinuria and glomerular injury scores, and increased glomerular area compared to their female counterparts at this age, but these parameters did not differ between Sham versus Uni‐X groups. When normalized to body weight, the remnant kidney was larger in male Uni‐X IUGR (4.76±0.35 mg/g; P<0.05) compared to male Sham IUGR (3.03±0.21), female Sham IUGR (3.05±0.10), and female Uni‐X IUGR (3.79±0.13), n=7/group, demonstrating greater renal hypertrophy in male IUGR offspring. GFR was significantly lower in male Uni‐X IUGR compared to female Uni‐X IUGR offspring at 19 months of age (0.49±0.10 versus 0.81±0.06 mL/min/g KW, males versus females respectively; P<0.05, n=9/group). Neutrophil gelatinase‐associated lipocalin, a urinary marker of distal tubular injury, was elevated in male Uni‐X IUGR offspring (59,871±18,697 ng/day; P<0.05) compared to male Sham IUGR (20,603±4,078) and female Uni‐X IUGR offspring (14,823±2,798), n=7/group. In addition, cortical mRNA expression of TNF‐α and TGF‐β was greater in male Uni‐X IUGR offspring compared to male Sham IUGR and male Uni‐X controls. These results demonstrate that IUGR leads to greater renal hypertrophy, distal tubular injury, and renal inflammation in response to a chronic renal insult during late adulthood in males. In summary, in addition to differences in kidney structure and injury that exist between men and women in the general population with aging, IUGR programs an additional sex difference in the renal response to a chronic renal insult in later life.Support or Funding InformationRO1HL074927, HL51971, P20GM104357, AHAGRNT19900004, T32HL105324, F30DK112718This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.