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KCNJ16-depleted kidney organoids recapitulate tubulopathy and lipid recovery upon statins treatment.
Sendino Garví, E; van Slobbe, G J J; Zaal, E A; de Baaij, J H F; Hoenderop, J G; Masereeuw, R; Janssen, M J; van Genderen, A M.
Afiliación
  • Sendino Garví E; Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Universiteitsweg 99, 3584 CG, Utrecht, The Netherlands.
  • van Slobbe GJJ; Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Universiteitsweg 99, 3584 CG, Utrecht, The Netherlands.
  • Zaal EA; Division of Cell Biology, Metabolism and Cancer, Department Biomolecular Health Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, Netherlands.
  • de Baaij JHF; Department of Medical BioSciences, Radboud University Medical Center, Nijmegen, Netherlands.
  • Hoenderop JG; Department of Medical BioSciences, Radboud University Medical Center, Nijmegen, Netherlands.
  • Masereeuw R; Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Universiteitsweg 99, 3584 CG, Utrecht, The Netherlands.
  • Janssen MJ; Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Universiteitsweg 99, 3584 CG, Utrecht, The Netherlands. Manoe.J.Janssen@radboudumc.nl.
  • van Genderen AM; Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Universiteitsweg 99, 3584 CG, Utrecht, The Netherlands. a.m.vangenderen@uu.nl.
Stem Cell Res Ther ; 15(1): 268, 2024 Aug 26.
Article en En | MEDLINE | ID: mdl-39183338
ABSTRACT

BACKGROUND:

The KCNJ16 gene has been associated with a novel kidney tubulopathy phenotype, viz. disturbed acid-base homeostasis, hypokalemia and altered renal salt transport. KCNJ16 encodes for Kir5.1, which together with Kir4.1 constitutes a potassium channel located at kidney tubular cell basolateral membranes. Preclinical studies provided mechanistic links between Kir5.1 and tubulopathy, however, the disease pathology remains poorly understood. Here, we aimed at generating and characterizing a novel advanced in vitro human kidney model that recapitulates the disease phenotype to investigate further the pathophysiological mechanisms underlying the tubulopathy and potential therapeutic interventions.

METHODS:

We used CRISPR/Cas9 to generate KCNJ16 mutant (KCNJ16+/- and KCNJ16-/-) cell lines from healthy human induced pluripotent stem cells (iPSC) KCNJ16 control (KCNJ16WT). The iPSCs were differentiated following an optimized protocol into kidney organoids in an air-liquid interface.

RESULTS:

KCNJ16-depleted kidney organoids showed transcriptomic and potential functional impairment of key voltage-dependent electrolyte and water-balance transporters. We observed cysts formation, lipid droplet accumulation and fibrosis upon Kir5.1 function loss. Furthermore, a large scale, glutamine tracer flux metabolomics analysis demonstrated that KCNJ16-/- organoids display TCA cycle and lipid metabolism impairments. Drug screening revealed that treatment with statins, particularly the combination of simvastatin and C75, prevented lipid droplet accumulation and collagen-I deposition in KCNJ16-/- kidney organoids.

CONCLUSIONS:

Mature kidney organoids represent a relevant in vitro model for investigating the function of Kir5.1. We discovered novel molecular targets for this genetic tubulopathy and identified statins as a potential therapeutic strategy for KCNJ16 defects in the kidney.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Organoides / Inhibidores de Hidroximetilglutaril-CoA Reductasas / Canales de Potasio de Rectificación Interna / Células Madre Pluripotentes Inducidas Límite: Humans Idioma: En Revista: Stem Cell Res Ther Año: 2024 Tipo del documento: Article País de afiliación: Países Bajos Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Organoides / Inhibidores de Hidroximetilglutaril-CoA Reductasas / Canales de Potasio de Rectificación Interna / Células Madre Pluripotentes Inducidas Límite: Humans Idioma: En Revista: Stem Cell Res Ther Año: 2024 Tipo del documento: Article País de afiliación: Países Bajos Pais de publicación: Reino Unido