Heart and iron deficiency anaemia in rats with renal insufficiency: The role of hepcidin

Aim: Anaemia is prevalent in chronic kidney disease (CKD) and induces significant changes in heart and kidney. In this study, we evaluated the relationship between iron metabolism, hepcidin and inflammation focusing on left ventricular (LV) function, in a remnant kidney rat model. Methods: Rats with 5/6 subtotal nephrectomy (STNx) and sham operation. Haemoglobin (Hb), serum iron (SI), fractional shortening (FS%) by echocardiograms were evaluated. Six months after STNx, the heart and kidney were processed by immunohistochemistry with antibodies against hypoxia-inducible factors (HIF)-1alpha, erythropoietin (EPO), pro-hepcidin, caspase-3, tumour necrosis factor (TNF)-alpha and interleukin (IL)-6. Results: Hb (g/dL) STNx: 10.8 +/- 0.8, sham: 14.7 +/- 0.6 (P < 0.01); SI (microg/dL) STNx: 154.5 +/- 24.5, sham: 287.5 +/- 32.1 (P < 0.01); heart weight (g) STNx: 2.21 +/- 0.15, sham: 1.12 +/- 0.12 (P < 0.01); FS% STNx: 28.4 +/- 2.5, sham: 45.1 +/- 4.1 (P < 0.01). There was a correlation between Hb and FS% (r = 0.95; P < 0.01) and between SI and FS% (r = 0.86; P < 0.01) in the STNx group. Tissue ferritin was reduced in heart and in kidney in the STNx group (P < 0.01). HIF-1alpha was expressed in cardiomyocytes (positive cells/area) STNx: 32 +/- 5, sham: 4 +/- 1; and tubular cells in STNx group: 70 +/- 16, sham: 10 +/- 3, P < 0.01. Hepcidin (% staining/area) in heart STNx: 6.6 +/- 0.8, sham: 0.8 +/- 0.1; in kidney STNx: 9.7 +/- 2.6, sham: 3.7 +/- 0.9, P < 0.01. EPO (% staining/area) in heart STNx: 2.6 +/- 0.4, sham: 0.8 +/- 0.2; in kidney STNx: 10.2 +/- 1.4, sham: 1.2 +/- 0.6; P < 0.01. In STNx group positive caspase-3, TNF-alpha and IL-6 were detected in heart and renal cells. Conclusion: Low LV performance is associated with iron deficiency anaemia in rats with CKD. Furthermore, overproduction of HIF-1alpha and the activation of caspase-3 seem to be associated with iron deficiency and with inflammatory markers. Hepcidin seems to plays a key role in this mechanism.