Open Research Projects, Research

Role of the SLC26A1 in kidney nutrient absorption and toxin excretion

Principle Investigator

Prof. Dr. Felix Knauf

Scientific interest within the context of the graduate college:

The kidney has a central role in absorbing nutrients for tissue function and health. Vice versa, cellular toxins have to be excreted by the kidney into the urine to avoid systemic accumulation and toxicity.1,2 Our working group recently described a patient who has a genetic defect of the sulfate transporter SLC26A1.3 SLC26A1 has been postulated to mediate sulfate absorption in exchange for oxalate. Sulfate is an important nutrient for musculoskeletal as well as cardiovascular health. Our patient described with a mutation of SLC26A1 has been suffering from a musculoskeletal disorder. Additional studies performed in large population cohorts (UK Biobank) have now shown that defective sulfate transport may be more common than expected and is related to bone fractures (manuscript in revision). We hypothesize that the anion exchanger SLC26A1 mediates sulfate (nutrient) absorption in the kidney for exchange of oxalate (toxin). In order to investigate this as part of a doctoral thesis, we have generated human pluripotent stem cells deficient for SLC26A1. The doctoral student will be culturing these stem cells to so called kidney organoids following a protocol established in our laboratory (Constantin Dickel, Re-Thinking Health, Class of 2022). The doctoral student will be performing transport studies using radioactive tracers and examine the effect of sulfate and oxalate transport defects on cellular toxicity (metabolomics, mitochondrial function).

Project description:

Introduction: The doctoral thesis will examine the hypothesis that SLC26A1 mediates sulfate absorption in exchange for oxalate using a kidney organoid model. In a first step, the doctoral student will be examining whether sulfate is taken up from kidney cells. In a second step, the doctoral student will be comparing kidney tubuloids from wild-type cells in comparison to cells deficient for SLC26A1. The doctoral student will be examining the effect of oxalate accumulation on cellular toxicity as measured by mitochondrial dysfunction. In case SLC26A1 mediates oxalate uptake from the basolateral membrane in exchange for sulfate, we predict that SLC26A1 deficiency will protect from cell death induced by oxalate due to impaired oxalate uptake into the cell. This may represent a novel pharmacological approach to protect the kidney from oxalate toxicity specifically for patients suffering from oxalate-related disorders. To this end, the following specific aims will be pursued:

Aim 1: Characterize sulfate and oxalate transport in kidney tubuloids from pluripotent stem cells.

Aim 2: Examine the effect of SLC26A1 deletion on cellular uptake of sulfate and oxalate.

Aim 3: Examine the effect of SLC26A1 deletion to prevent from oxalate toxicity and cell death.

References

  1. Novarino G, Weinert S, Rickheit G, Jentsch TJ. Endosomal chloride-proton exchange rather than chloride conductance is crucial for renal endocytosis. Science. 2010; 328(5984):1398-1401.
  2. Knauf F, Yang CL, Thomson RB, Mentone SA, Giebisch G, Aronson PS. Identification of a chloride-formate exchanger expressed on the brush border membrane of renal proximal tubule cells. Proc Natl Acad Sci U S A. 2001; 98(16):9425-9430.
  3. Pfau A, Lopez-Cayuqueo KI, Scherer N, Wuttke M, Wernstedt A, Gonzalez Fassrainer D, […], Kottgen A, Jentsch TJ, Knauf F. SLC26A1 is a major determinant of sulfate homeostasis in humans. J Clin Invest. 2023; 133(3):e161849.