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Mechanism and reversal of drug-induced nephrotoxicity on a chip.
Cohen, Aaron; Ioannidis, Konstantinos; Ehrlich, Avner; Regenbaum, Shaun; Cohen, Merav; Ayyash, Muneef; Tikva, Sigal Shafran; Nahmias, Yaakov.
Afiliação
  • Cohen A; Grass Center for Bioengineering, Benin School of Computer Science and Engineering, The Hebrew University of Jerusalem, Jerusalem 91904, Israel.
  • Ioannidis K; Department of Cell and Developmental Biology, Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem 91904, Israel.
  • Ehrlich A; Grass Center for Bioengineering, Benin School of Computer Science and Engineering, The Hebrew University of Jerusalem, Jerusalem 91904, Israel.
  • Regenbaum S; Grass Center for Bioengineering, Benin School of Computer Science and Engineering, The Hebrew University of Jerusalem, Jerusalem 91904, Israel.
  • Cohen M; Department of Cell and Developmental Biology, Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem 91904, Israel.
  • Ayyash M; Grass Center for Bioengineering, Benin School of Computer Science and Engineering, The Hebrew University of Jerusalem, Jerusalem 91904, Israel.
  • Tikva SS; Tissue Dynamics, Jerusalem 91904, Israel.
  • Nahmias Y; Grass Center for Bioengineering, Benin School of Computer Science and Engineering, The Hebrew University of Jerusalem, Jerusalem 91904, Israel.
Sci Transl Med ; 13(582)2021 02 24.
Article em En | MEDLINE | ID: mdl-33627489
ABSTRACT
The kidney plays a critical role in fluid homeostasis, glucose control, and drug excretion. Loss of kidney function due to drug-induced nephrotoxicity affects over 20% of the adult population. The kidney proximal tubule is a complex vascularized structure that is particularly vulnerable to drug-induced nephrotoxicity. Here, we introduce a model of vascularized human kidney spheroids with integrated tissue-embedded microsensors for oxygen, glucose, lactate, and glutamine, providing real-time assessment of cellular metabolism. Our model shows that both the immunosuppressive drug cyclosporine and the anticancer drug cisplatin disrupt proximal tubule polarity at subtoxic concentrations, leading to glucose accumulation and lipotoxicity. Impeding glucose reabsorption using glucose transport inhibitors blocked cyclosporine and cisplatin toxicity by 1000- to 3-fold, respectively. Retrospective study of 247 patients who were diagnosed with kidney damage receiving cyclosporine or cisplatin in combination with the sodium-glucose cotransporter-2 (SGLT2) inhibitor empagliflozin showed significant (P < 0.001) improvement of kidney function, as well as reduction in creatinine and uric acid, markers of kidney damage. These results demonstrate the potential of sensor-integrated kidney-on-chip platforms to elucidate mechanisms of action and rapidly reformulate effective therapeutic solutions, increasing drug safety and reducing the cost of clinical and commercial failures.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Preparações Farmacêuticas / Inibidores do Transportador 2 de Sódio-Glicose Idioma: En Ano de publicação: 2021 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Preparações Farmacêuticas / Inibidores do Transportador 2 de Sódio-Glicose Idioma: En Ano de publicação: 2021 Tipo de documento: Article