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Abstract: TH-PO561

Cystathionine-Gamma-Lyase Deficiency Protects Against Calcium Oxalate Nephropathy

Session Information

Category: Bone and Mineral Metabolism

  • 401 Bone and Mineral Metabolism: Basic

Authors

  • Lu, Yimin, University of Lausanne, Lausanne, Switzerland
  • Ramakrishnan, Suresh Krishna, University of Lausanne, Lausanne, Switzerland
  • Auberson, Muriel, University of Lausanne, Lausanne, Switzerland
  • Durussel, Fanny, University of Lausanne, Lausanne, Switzerland
  • Bonny, Olivier, Lausanne University Hospital, Lausanne, Switzerland
Background

Cystathionine-gamma-lyase (CSE), along with cystathionine-beta-synthase (CBS) and 3-mercaptopyruvate sulfurtransferase (3-MPST) contribute to the production of the gazotransmitter hydrogen sulfide (H2S) in various tissues. In the kidney, CSE is expressed in the cortex and in the outer stripe of the outer medulla, but its role remains elusive. Recent studies using pharmacological inhibition of CSE, or CSE deficient mice, have suggested a pro-inflammatory role of H2S in various inflammatory mouse models. Moreover, administration of H2S donor worsened the inflammation in these models. Here, we explored the role of CSE in a recently established mouse model of renal calcium oxalate crystallopathy.

Methods

CSE-deficient (Cse-/-) mice were obtained from Dr. Ishii (Showa Pharmaceutical University, Tokyo, Japan). Eight-week old Cse+/+ or Cse-/- male mice were allocated to either 1.5% calcium plus 1.5% hydroxyproline-enriched diet or to control diet for 3 weeks. Mice were kept in metabolic cages for 24h urine collection before termination of the experiments. Indirect methylene blue method was used to measure H2S producing capacity of renal tissue. Crystal deposits were assessed by Pizzolato staining, and fibrosis and inflammation by trichrome staining. Fibrosis and inflammation parameters were further evaluated by qPCR.

Results

At baseline, Cse-/- mice have suppressed Cse mRNA expression, but unaffected levels of Cbs and 3-Mpst in kidney tissue. Kidneys of Cse-/- mice had reduced H2S producing capacity compared to Cse+/+ littermates. Renal morphology and function were normal at baseline in both genotypes. After three weeks exposure to calcium-hydroxyproline-enriched diet, Cse+/+ mice displayed significantly higher serum creatinine and blood urea nitrogen levels, while Cse-/- mice had normal renal function. Cse-/- mice had decreased crystal deposits, lower inflammation and fibrosis, as assessed by histomorphology and qPCR. Crystal-adherent proteins were less expressed in Cse-/- mice and in primary culture of proximal tubules exposed to calcium-oxalate crystals.

Conclusion

CSE deficiency protects from inflammation and fibrosis in a model of renal calcium oxalate crystallopathy, and preserves renal function. Collectively, our data show that H2S-producing enzymes might be suitable pharmacological targets for calcium-oxalate nephropathy.

Funding

  • Government Support - Non-U.S.