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Abstract: TH-OR008

Renal Inflammation, Vascular Pathology, and Splenomegaly Are Induced in a Mouse Model of Spontaneous Chronic Metabolic Acidosis

Session Information

Category: Fluid and Electrolytes

  • 901 Fluid and Electrolytes: Basic

Authors

  • Verlander, Jill W., University of Florida, Gainesville, Florida, United States
  • Chen, Chao, University of Florida, Gainesville, Florida, United States
  • Matthews, Sharon W., University of Florida, Gainesville, Florida, United States
  • Harris, Autumn N., University of Florida, Gainesville, Florida, United States
  • Lee, Hyun-Wook, University of Florida, Gainesville, Florida, United States
  • Valero, Maria carmen, University of Florida, Gainesville, Florida, United States
  • Romero, Michael F., Mayo Clinic College of Medicine, Rochester, Minnesota, United States
  • Clapp, William L., University of Florida, Gainesville, Florida, United States
  • Weiner, I. David, University of Florida, Gainesville, Florida, United States
Background

Recent studies have shown that alkali treatment retards the progression of chronic kidney disease. However, whether long-term metabolic acidosis alone can cause development and progression of renal and vascular pathology is not known. We used a model of spontaneous chronic metabolic acidosis to examine this issue.

Methods

We used 4 and 8 month old female mice with proximal tubule NaHCO3- cotransporter, NBCe1-A, deletion (KO) and their WT littermates. We used immunohistochemistry to determine inflammatory cell type (macrophage/monocyte, F4/80; B lymphocyte, B220; T lymphocyte, CD3).

Results

At both 4 and 8 mo KO mice had marked metabolic acidosis (4 mo, serum HCO3- WT, 25.4±0.8 vs KO, 12.5±1.5, n=4 per group; 8 mo, WT 21.8±1.5 vs KO 11.2±0.5 n=5 and 4). Urine albumin, measured at 8 mo, was increased significantly (WT 19.1±11.3 mg/d; KO 56.8±9.7, P<0.02); urea clearance was unaltered. Toluidine blue-stained semi-thin sections and transmission electron microscopy showed mesangial expansion with increased mesangial matrix deposition in KO at 4 and 8 mo compared to WT. Trichrome and picrosirius red stains showed mild-to-moderate increase in interstitial collagen in KO at 4 mo and 8 mo. Routine light microscopy showed mild cellular infiltrates, particularly in perivascular regions, in 4 mo KO kidney that was markedly increased at 8 mo. There was an increase in interstitial macrophages in KO cortex at 4 mo that was accentuated at 8 mo. The perivascular infiltrate in 8 mo KO kidney was predominantly T lymphocytes, but also included B lymphocytes and macrophages. The thoracic aorta had increased wall thickness with thickening and fragmentation of the elastin layers in 4 and 8 mo KO mice. KO mice had marked splenomegaly, which appeared due predominantly to increased macrophages in the splenic parenchyma.

Conclusion

Long-term metabolic acidosis induced by NBCe1-A deletion causes significant inflammatory activation, with renal inflammatory infiltrates and expansion of the splenic macrophage/monocyte population, along with development of mild mesangial expansion, renal interstitial fibrosis, and vascular defects. These data suggest chronic metabolic acidosis may independently contribute to the development and progression of renal and vascular disease.

Funding

  • NIDDK Support