Mechanisms of intracellular iron dysregulation in kidney fibrosis and reno-protective strategies

Chronic kidney disease (CKD) affects 10-15% of the population worldwide.

More than 37 million people are estimated to have CKD in the US, and 2 in every 1000 Americans need dialysis or a kidney transplant to survive. Anemia and dysfunctional iron homeostasis frequently complicate CKD. Kidney fibrosis is the final mechanism common for all progressive kidney disorders leading to CKD.

However, very few therapies are available to slow the progression of kidney fibrosis in CKD patients.

Our long-term goal is to identify novel actionable drivers of kidney fibrosis, so that they can be therapeutically targeted to delay progression of CKD.

Proximal tubular epithelial cells represent the key cell population implicated in the pathophysiology of kidney fibrosis and may accumulate iron in CKD.

The overall objective of this proposal is to define the role of iron homeostasis in responses of these cells to fibrosis, which are responsible for CKD progression. Based on our preliminary data, we hypothesize that in CKD, tubular cells are highly sensitive to labile iron.

Nonetheless, the following two cytoprotective mechanisms initially limit tubular iron toxicity in CKD by preventing an uncontrolled expansion of the tubular labile iron pool: (1) induction of tubular iron export and (2) induction of intracellular storage of iron within the tubular cells. We expect that these protective mechanisms fail during iron supplementation unless they are enhanced therapeutically.

This hypothesis will be tested in two sets of experiments that will increase or decrease labile iron pool in tubular cells, and we will define the consequential changes of tubular injury, survival, and fibrosis that constitute the disease progression.

Studies will be facilitated by induction of CKD in our mutant mice lacking critical iron-related proteins in proximal tubules (ferritin-H, responsible for iron storage and ferroportin, responsible for iron removal from cells) and established protocols for iron supplementation, restriction, and conservative therapeutic chelation.

Successful completion of this work is expected to elucidate the fundamental mechanisms of intracellular iron regulation in the kidney, which are critical for kidney fibrosis propagation and will identify approaches capable of influencing cellular catalytic iron as a novel therapeutic target.

Thus, the proposed work addresses a critical lack of knowledge essential for the development of new therapeutic approaches to iron homeostasis, which are on the critical path to halting CKD progression in patients.