Macrophage and epithelial cell H-ferritin expression regulates renal inflammation

Abstract

Inflammation culminating in fibrosis contributes to progressive kidney disease. Crosstalk between the tubular epithelium and interstitial cells regulates inflammation by a coordinated release of cytokines and chemokines. Here we studied the role of heme oxygenase-1 (HO-1) and the heavy subunit of ferritin (FtH) in macrophage polarization and renal inflammation. Deficiency in HO-1 was associated with increased FtH expression, accumulation of macrophages with a dysregulated polarization profile, and increased fibrosis following unilateral ureteral obstruction in mice; a model of renal inflammation and fibrosis. Macrophage polarization in vitro was predominantly dependent on FtH expression in isolated bone marrow-derived mouse monocytes. Utilizing transgenic mice with conditional deletion of FtH in the proximal tubules (FtHPT−/−) or myeloid cells (FtHLysM−/−), we found that myeloid FtH deficiency did not affect polarization or accumulation of macrophages in the injured kidney compared to wild-type (FtH+/+) controls. However, tubular FtH deletion led to a marked increase in pro-inflammatory macrophages. Furthermore, injured kidneys from FtHPT−/− mice expressed significantly higher levels of inflammatory chemokines and fibrosis compared to kidneys from FtH+/+ and FtHLysM−/− mice. Thus, there are differential effects of FtH in macrophages and epithelial cells, which underscores the critical role of FtH in tubular-macrophage crosstalk during kidney injury.

Heme Oxygenase 1 as a Therapeutic Target in Acute Kidney Injury

“…33, 36 These findings were recapitulated using an animal model of unilateral ureteral obstruction, highlighting the salutary effect of HO-1 in the immune responses during AKI. 37, 38 …”

Heme Oxygenase-1 in Kidney Health and Disease

“…HO activity is beneficial in oxidative stress due to production of antioxidant bilirubin (57) and vasodilatory CO (55,69), both of which are anti-inflammatory. In addition, induction of HO-1 is associated with increased Ft levels, which exhibits anti-inflammatory effects as well (23).…”

“…This review will update the reader on new findings regarding the role of HO in kidney homeostasis and pathology. induces ferritin (Ft), which is protective (23). While each product exhibits beneficial properties, potential adverse effects may result if they reach high levels (Fig.…”

Most Important Cellular Changes Involved in Renal Ischemia Reperfusion Injury and the Consequent Impact on Selected Remote Organs

“…2. Inflammatory nature of the injured kidneys whichmay produces clearly higher inflammatory chemokines expression and renal fibrosis 59 as well as oxidative stress by disturbing systemic iron homeostasis 60 . This inflammatory process may eventually transform into systemic inflammatory reaction mediating remote organ injury 61 .…”

“…3. A great modulating effect on the remote organ injury would be induced by the disturbance of cytokine/chemokine homeostasis in AKI, which may be attributable to the decreased renal clearance and/or increased production of these cytokine/ chemokine 59,60,62 . 4.…”