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Novel perspectives regarding the physiologic mechanisms by which gliflozins induce reticulocytosis and erythrocytosis.
Heyman, Samuel N; Armaly, Zaher; Hamo-Giladi, Dalit B; Abassi, Zaid.
Afiliação
  • Heyman SN; Department of Medicine, Hadassah Hebrew University Hospital, Mt. Scopus and Herzog Hospital, Jerusalem, Israel.
  • Armaly Z; Department of Nephrology, Nazareth Hospital-EMMS, Nazareth and the Azrieli Faculty of Medicine, Bar Ilan University, Safed, Israel.
  • Hamo-Giladi DB; Ruth & Bruce Rappaport Faculty of Medicine, Technion-IIT, Haifa, Israel.
  • Abassi Z; Ruth & Bruce Rappaport Faculty of Medicine, Technion-IIT, Haifa, Israel.
Am J Physiol Endocrinol Metab ; 325(5): E621-E623, 2023 11 01.
Article em En | MEDLINE | ID: mdl-37819195
Gliflozins provide a breakthrough in the management of type-2 diabetes. In addition to facilitating normoglycemia, these sodium-glucose cotransporter type 2 (SGLT2) inhibitors attenuate obesity, hypertension, dyslipidemia, and fluid retention, reduce cardiovascular morbidity, retard the progression of renal dysfunction, and improve survival. The administration of gliflozins also triggers erythropoietin (EPO) production, with the consequent induction of reticulocytosis and erythrocytosis. The mechanism(s) by which gliflozins induce erythropoiesis is a matter of debate. Whereas the canonical pathway of triggering EPO synthesis is through renal tissue hypoxia, it has been suggested that improved renal oxygenation may facilitate EPO synthesis via noncanonical trails. The latter proposes that recovery of peritubular interstitial fibroblasts producing erythropoietin (EPO) is responsible for enhanced erythropoiesis. According to this hypothesis, enhanced glucose/sodium reuptake by proximal tubules in uncontrolled diabetes generates cortical hypoxia, with injury to these cells. Once transport workload declines with the use of SGLT2i, they recover and regain their capacity to produce EPO. In this short communication, we argue that this hypothesis is incorrect. First, there is no evidence for interstitial cell injury related to hypoxia in the diabetic kidney. Tubular, rather than interstitial cells are prone to hypoxic injury in the diabetic kidney. Moreover, hypoxia, not normoxia, stimulates EPO synthesis by hypoxia-inducible factors (HIFs). Hypoxia regulates EPO synthesis as it blocks HIF prolyl hydroxylases (that initiate HIF alpha degradation), hence stabilizing HIF signals, inducing HIF-dependent genes, including EPO located in the deep cortex, and its production is initiated by the apocrinic formation of HIF-2, colocalized in these same cells.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Policitemia / Eritropoetina / Nefropatias Diabéticas / Inibidores do Transportador 2 de Sódio-Glicose Limite: Humans Idioma: En Revista: Am J Physiol Endocrinol Metab Assunto da revista: ENDOCRINOLOGIA / FISIOLOGIA / METABOLISMO Ano de publicação: 2023 Tipo de documento: Article País de afiliação: Israel

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Policitemia / Eritropoetina / Nefropatias Diabéticas / Inibidores do Transportador 2 de Sódio-Glicose Limite: Humans Idioma: En Revista: Am J Physiol Endocrinol Metab Assunto da revista: ENDOCRINOLOGIA / FISIOLOGIA / METABOLISMO Ano de publicação: 2023 Tipo de documento: Article País de afiliação: Israel