Abstract
Kidney iron deposition may play a role in the progression of tubulointerstitial injury during chronic kidney disease. Here, we studied the molecular mechanisms of kidney iron loading in experimental focal segmental glomerulosclerosis (FSGS) and investigated the effect of iron-reducing interventions on disease progression. Thy-1.1 mice were injected with anti-Thy-1.1 monoclonal antibody (mAb) to induce proteinuria. Urine, blood and tissue were collected at day (D)1, D5, D8, D15 and D22 after mAb injection. Thy-1.1 mice were subjected to captopril (CA), iron-deficient (ID) diet or iron chelation (deferoxamine; DFO). MAb injection resulted in significant albuminuria at all time points (p < 0.01). Kidney iron loading, predominantly in distal tubules, increased in time, along with urinary kidney injury molecule-1 and 24p3 concentration, as well as kidney mRNA expression of Interleukin-6 (Il-6) and Heme oxygenase-1 (Ho-1). Treatment with CA, ID diet or DFO significantly reduced kidney iron deposition at D8 and D22 (p < 0.001) and fibrosis at D22 (p < 0.05), but not kidney Il-6. ID treatment increased kidney Ho-1 (p < 0.001). In conclusion, kidney iron accumulation coincides with progression of tubulointerstitial injury in this model of FSGS. Reduction of iron loading halts disease progression. However, targeted approaches to prevent excessive kidney iron loading are warranted to maintain the delicate systemic and cellular iron balance.
Highlights
Kidney iron deposition may play a role in the progression of tubulointerstitial injury during chronic kidney disease
Periodic Acid Schiff (PAS) staining showed progressive kidney injury in monoclonal antibody (mAb)-injected mice characterized by tubular dilatation and intratubular protein casts at day 1 (D1) through D22 (Fig. 1c), and glomerular sclerosis from D8 onward
Kidney iron loading has been demonstrated in proteinuric kidney diseases, but insights into the molecular mechanisms of iron accumulation and its contribution to progression of kidney injury remained elusive
Summary
Kidney iron deposition may play a role in the progression of tubulointerstitial injury during chronic kidney disease. We studied the molecular mechanisms of kidney iron loading in experimental focal segmental glomerulosclerosis (FSGS) and investigated the effect of iron-reducing interventions on disease progression. One clinical study to date reported a beneficial effect of iron chelation by deferiprone in patients with biopsy-proven glomerulopathy and diabetic nephropathy, leading to reduced proteinuria[30]. From this study it could not be concluded whether chelation prevented disease progression. A targeted approach to reduce kidney tubular iron loading might be necessary for chronic treatment of CKD patients, since long-term chelation therapy is associated with nephrotoxicity[31]
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