Association between renal iron accumulation and renal interstitial fibrosis in a rat model of chronic kidney disease

Abstract

Iron accumulation is associated with the pathophysiology of chronic kidney disease (CKD). Renal fibrosis is a final common feature that contributes to the progression of CKD; however, little is known about the association between renal iron accumulation and renal interstitial fibrosis in CKD. Here we investigate the effects of iron chelation on renal interstitial fibrosis in a rat model of CKD. CKD was induced by 5/6 nephrectomy in Sprague-Dawley rats. At 8 weeks after operation, 5/6 nephrectomized rats were administered an oral iron chelator, deferasirox (DFX), in chow for 8 weeks. Other CKD rats were given a normal diet. Sham-operative rats given a normal diet served as a control. CKD rats exhibited hypertension, glomerulosclerosis and renal interstitial fibrosis. Iron chelation with DFX did not change hypertension and glomerulosclerosis; however, renal interstitial fibrosis was attenuated in CKD rats. Consistent with these findings, renal gene expression of collagen type III and transforming growth factor-β was increased in CKD rats compared with the controls, while iron chelation suppressed these increments. In addition, a decrease in vimentin along an increase in E-cadherin in renal gene expression was observed in CKD rats with iron chelation. CKD rats also showed increased CD68-positive cells in the kidney, whereas its increase was attenuated by iron deprivation. Similarly, increased renal gene expression of CD68, tumor necrosis factor-α and monocyte chemoattractant protein-1 was suppressed in CKD rats with iron chelation. Renal iron accumulation seems to be associated with renal interstitial fibrosis in a rat model of CKD.

Longitudinal assessment of rabbit renal fibrosis induced by unilateral ureteral obstruction using two‐dimensional susceptibility weighted imaging

“…18,19 Although the results of our study demonstrated that a good correlation with histologic fibrosis scores was present. First, the contralateral kidney of rabbits (right kidney) was not studied because of rabbits' inherent anatomy, which includes a large stomach and many intestinal tubes around the right kidney leading to severe susceptibility artifacts, although several measurements were taken to reduce the artifacts.…”

“…Furthermore, the renal perfusion and hypoxia play roles in renal fibrosis, which have been confirmed in previous studies. 18,19 Although the results of our study demonstrated that a good correlation with histologic fibrosis scores was present. The potential influences of these factors will be exploited in the future.…”

“…Previous studies confirmed that iron deposition, ischemia, and hypoxia were related to renal fibrosis. 18,19 A recent study has confirmed that the alteration of signal on SWI was independently associated with increasing stages of liver fibrosis in the multiple regression analysis. 20 Based on the aforementioned theory, SWI is assumed to be highly sensitive to fibrotic alterations in renal fibrosis.…”

Iron suppresses erythropoietin expression via oxidative stress-dependent hypoxia-inducible factor-2 alpha inactivation

“…Consistent with the association between renal fibrosis and iron accumulation, several studies have shown that iron content is increased in fibrotic kidneys of the angiotensin II-infused rat, 32 Dahl salt-sensitive rat, 33 and 5/6 nephrectomized rat. 34 We, and others, have shown the antifibrotic effect of tissue iron reduction using iron chelators or iron restriction chow on the kidney. 15,33,34 Here, direct SFO treatment diminished renal EPO expression in the kidney with increased iron content.…”

“…34 We, and others, have shown the antifibrotic effect of tissue iron reduction using iron chelators or iron restriction chow on the kidney. 15,33,34 Here, direct SFO treatment diminished renal EPO expression in the kidney with increased iron content. Therefore, there is a close relationship between iron accumulation and renal fibrosis, resulting in the reduction of EPO expression.…”