In an earlier issue of Blood Red Cells & Iron, Zhang et al1 presented a novel finding: severe iron deficiency induces systemic inflammation and renal and cardiac fibrosis in a mouse model of chronic kidney disease (CKD), without significantly worsening inflammation and injury in the kidney and heart. This study identified iron deficiency as a potentially strong risk factor for increased fibrosis in the kidney and heart in CKD.
CKD, characterized by progressive damage and eventual loss of kidney function, is one of the most prevalent and life-threatening diseases. Anemia is commonly observed in patients with CKD due to impaired erythropoiesis (a process responsible for red blood cell production), iron deficiency, shortened red blood cell life span, and inflammation. Compelling evidence suggests a positive correlation between anemia and CKD severity. It has been reported that lower time-averaged hemoglobin levels (<12 g/dL) are associated with an increased risk of end-stage renal disease in male patients with CKD.2 Anemia in CKD can also elevate the risk of developing cardiovascular diseases (CVDs), including left ventricular hypertrophy and heart failure.3,4 Therefore, correcting anemia is expected to potentially slow CKD progression and associated cardiovascular events, thereby improving patients’ quality of life and survival. Most clinical studies have shown beneficial effects of anemia correction, particularly in patients with early-stage CKD with a hemoglobin level <10 g/dL.5,6 Erythropoiesis-stimulating agents, in combination with iron therapy, remain the primary treatment for CKD-associated anemia. However, despite strong evidence of the adverse effects of anemia on CKD progression and cardiovascular complications, the exact pathological changes in the kidney and heart, as well as the underlying causes (eg, iron deficiency, hypoxia, or inflammation), remain poorly understood.
In this study, Zhang et al used 2 CKD mouse models: an adenine-induced nephropathy model and Col4a3 knockout mice, which develop progressive kidney dysfunction. These models were used to induce moderate iron deficiency via a low-iron diet or severe iron deficiency through a 1-time phlebotomy combined with a low-iron diet. The moderate iron deficiency regimen, although effective in control mice, failed to cause tissue iron depletion (except in the kidney) or worsen the already impaired erythropoiesis in adenine-treated mice. Furthermore, the moderate iron deficiency regimen did not significantly exacerbate renal dysfunction, systemic inflammation, or local inflammation in the kidney and heart in either CKD model. In contrast, severe iron deficiency caused significant iron depletion in multiple tissues, including the liver, spleen, kidney, and heart, and leads to greater systemic hypoxia in adenine-induced CKD, despite the absence of a significant drop in hemoglobin level or hematocrit. Notably, severe iron deficiency increased systemic inflammation and the expression of fibrosis-related genes in the kidney and heart of adenine-treated mice. However, it did not promote local inflammation in the kidney and heart, nor did it worsen renal dysfunction or cardiac hypertrophy.
The findings by Zhang et al have important clinical implications, suggesting that iron deficiency in the kidney and heart is a strong risk factor for the development of renal and cardiac fibrosis, independent of tissue inflammation severity. Although iron deficiency for up to 12 weeks did not exacerbate adenine-induced severe kidney dysfunction, it remains possible that prolonged iron deficiency could worsen renal injury and filtration capacity. Moreover, the negative effects of iron deficiency on kidney and cardiovascular function may be more pronounced in early to mid-stages of CKD. Despite the important observation of increased renal and cardiac fibrosis and systemic inflammation under severe iron deficiency in CKD, many questions remain, particularly regarding the mechanisms by which iron deficiency induces fibrogenesis. Inflammation, a known driver of fibrosis, was not significantly different in the kidney and heart of adenine-treated mice. Therefore, it is less likely that it plays a primary role in this scenario.
Zhang et al suggest that macrophage iron deficiency may contribute to increased fibrogenesis. This speculation is partly supported by a previous study showing that iron-deficient macrophages can drive fibrosis via intracellular oxidative stress and that restoring macrophage iron levels reduces fibrosis.7 However, the same study reported that iron-deficient macrophages are more inflammatory, as indicated by increased cytokine production, contrasting with the findings of Zhang et al of no significant changes in kidney or heart inflammation. Elevated systemic inflammation may contribute to fibrosis in the kidney and heart, but it is unclear whether circulating cytokines differ in profile or abundance from those produced locally.
Renal pericytes and cardiac fibroblasts, upon activation and transformation into myofibroblasts, play key roles in extracellular matrix production and fibrosis in the kidney and heart, respectively.8,9 Iron deficiency induces mitochondria-dependent oxidative stress, endoplasmic reticulum stress, and impaired autophagy.10 It would be valuable to determine in future studies whether iron deficiency occurs in renal pericytes and cardiac fibroblasts and induces their transdifferentiation into myofibroblasts dependent on stress-induced reprogramming (eg, epigenetic/transcriptomic and metabolic), along with the external cues such as transforming growth factor β. Because increased hypoxia is also observed in adenine-induced CKD with severe iron deficiency, it remains possible that hypoxia signaling contributes to this transformation, promoting renal and cardiac fibrosis. A better understanding of the molecular mechanisms underlying iron deficiency–induced fibrogenesis could lead to novel therapeutic strategies to slow or prevent the progression of kidney dysfunction and CVDs in CKD.
Conflict-of-interest: The author declares no competing financial interests.
