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Abstract: FR-PO1004

2,4-Dihydroxybenzoic Acid Improves Survival and Demonstrates a Renoprotective Effect in a Podocyte-Specific Coq8b-Knockout Mouse Model of Nephrotic Syndrome

Session Information

Category: Genetic Diseases of the Kidney

  • 1002 Genetic Diseases of the Kidney: Non-Cystic

Authors

  • Widmeier, Eugen, Boston Children's Hospital, Harvard Medical School, Boston, United States
  • Nakayama, Makiko, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, United States
  • Hugo, Hannah, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, United States
  • Yu, Seyoung, Yonsei University, Seoul, Korea (the Republic of)
  • Gee, Heon Yung, Yonsei University College of Medicine, Boston, Korea (the Republic of)
  • Hildebrandt, Friedhelm, Boston Children's Hospital, Brookline, Massachusetts, United States
Background

Steroid resistant nephrotic syndrome (SRNS) inevitably progresses to end-stage renal disease (ESRD) within the first three decades of life, requiring dialysis or transplantation for survival. Human mutations in the COQ8B gene (known also as ADCK4 - aarF domain containing kinase 4) cause SRNS (Ashraf JCI 123:5179, 2013). To study the function of COQ8B in podocytes we generated a podocyte specific Coq8b-knockout mouse model

Methods

Nphs2.Cre mice were crossed with Coq8blox/lox mice, to generate podocyte specific Coq8b knockout mice (Coq8bΔPodocyte) on a C57BL/6 background. Treatment with 2,4-dihydroxybenzoic acid (2,4-diHB) at 25 mM in the drinking water was started at 3 months of age. Kidneys were harvested for histological and ultrastructural analysis at 9 months in the untreated cohort and at 13 month in the cohort under treatment. Blood and urine were collected monthly for metabolic studies

Results

Coq8bΔPodocyte mice displayed onset of proteinuria at 4 months. Non-treated Coq8bΔPodocyte mice displayed a significant reduction in survival (40% alive) being moribund at 12 months of age progressing to ESRD (n=15). In contrast, Coq8bΔPodocyte mice treated with 2,4-diHB (n=12) showed significantly improved survival (100% alive), comparable to their untreated Coq8bΔPodocyte and wild type littermates. Histological analysis of Coq8bΔPodocyte kidneys at 9 months demonstrated severe global and focal segmental glomerular sclerosis (FSGS) with extensive interstitial fibrosis and tubular atrophy. Electron microscopy studies revealed severe foot process effacement and disturbed podocyte cell morphology. In contrast, treatment of Coq8bΔPodocyte mice with 2,4-diHB significantly reduced the levels of proteinuria and prevented the development of FSGS as well as foot process effacement maintaining normal renal function in treated mice at 13 months (n=12)

Conclusion

Our data demonstrate that 2,4-diHB, metabolite that functions to bypass the hydroxylation step mediated by Coq7 of the CoQ10 biosynthesis pathway efficiently ameliorates proteinuria and prevents FSGS in Coq8bΔPodocyte mice. Further, our study reveals a potential novel treatment option in 2,4-diHB for human SRNS caused by dysfunction in the CoQ10 biosynthesis pathway

Funding

  • Other NIH Support