Chronic Kidney Disease Induced by Cisplatin, Folic Acid and Renal Ischemia Reperfusion Induces Anemia and Promotes GATA-2 Activation in Mice

• Main Authors: Gabriel Rufino Estrela, Leandro Ceotto Freitas-Lima, Alexandre Budu, Adriano Cleis de Arruda, Mauro Sergio Perilhão, Ricardo Ambrósio Fock, Jonatan Barrera-Chimal, Ronaldo Carvalho Araújo
• Format: Article
• Language: English
• Published: MDPI AG 2021-07-01
• Series: Biomedicines
• Subjects: chronic kidney disease; anemia; experimental disease model
• Online Access: https://www.mdpi.com/2227-9059/9/7/769

Anemia is a common feature of chronic kidney disease (CKD). It is a process related to erythropoietin deficiency, shortened erythrocyte survival, uremic erythropoiesis inhibitors, and disordered iron homeostasis. Animal models of CKD-induced anemia are missing and would be desirable in order to study anemia mechanisms and facilitate the development of novel therapeutic tools. We induced three different models of CKD in mice and evaluated the development of anemia characteristics. Mice were subjected to unilateral ischemia-reperfusion or received repeated low doses of cisplatin or folic acid to induce nephropathy. Renal function, kidney injury and fibrotic markers were measured to confirm CKD. Moreover, serum hemoglobin, ferritin and erythropoietin were analyzed. Renal mRNA levels of <i>HIF-2α</i>, erythropoietin, hepcidin, <i>GATA-2</i>, and <i>GATA-2</i> target genes were also determined. All three CKD models presented increased levels of creatinine, urea, and proteinuria. Renal up-regulation of <i>NGAL</i>, <i>KIM-1</i>, and <i>TNF-α</i> mRNA levels was observed. Moreover, the three CKD models developed fibrosis and presented increased fibrotic markers and α-SMA protein levels. CKD induced decreased hemoglobin and ferritin levels and increased erythropoietin levels in the serum. Renal tissue showed decreased erythropoietin and <i>HIF-2α</i> mRNA levels, while an increase in the iron metabolism regulator hepcidin was observed. <i>GATA-2</i> transcription factor (erythropoietin repressor) mRNA levels were increased in all CKD models, as well as its target genes. We established three models of CKD-induced anemia, regardless of the mechanism and severity of kidney injury.