Abstract
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 HIF-2α, erythropoietin, hepcidin, GATA-2, and GATA-2 target genes were also determined. All three CKD models presented increased levels of creatinine, urea, and proteinuria. Renal up-regulation of NGAL, KIM-1, and TNF-α 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 HIF-2α mRNA levels, while an increase in the iron metabolism regulator hepcidin was observed. GATA-2 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.
Highlights
The prevalence of chronic kidney disease (CKD) is about 13% worldwide, which accounts for an estimated 850 million affected individuals [1]
The establishment of CKD was in all three models, as evidenced by the significant increases in plasma creatinine (Figure 1A), urea (Figure 1B), and proteinuria (Figure 1C) levels in the folic acid- and cisplatin-treated mice, as well as in those with CKD induced by ischemia-reperfusion
Anemia in CKD reduces the quality of life and increases the susceptibility to hospitalization and mortality [12]
Summary
The prevalence of chronic kidney disease (CKD) is about 13% worldwide, which accounts for an estimated 850 million affected individuals [1]. When an acute insult occurs, several tissue repair mechanisms are capable of restoring renal function. This wound healing process consists of consecutive events, such as acute. Recent single nucleus sequencing studies identified that after an acute kidney injury, a subpopulation of proximal tubular epithelial cells fail to repair, increasing the expression of pro-inflammatory and profibrotic mediators, contributing to fibrogenesis and CKD progression [8]. This process presents itself with glomerulosclerosis, vascular rarefaction, and tubulointerstitial fibrosis [4]. Interstitial spaces are filled with fibrillar material constituted of fibronectin, type I, and type III collagen [10,11]
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