PROJECT SUMMARY/ABSTRACT
Up to 90% of chronic kidney disease (CKD) patients exhibit hypertension, which accelerates kidney damage
and kidney function decline. Despite many anti-hypertensive drugs, blood pressure (BP) often remains
uncontrolled. In fact, CKD is the strongest predictor of treatment-resistant hypertension. Critically, CKD is a
silent killer: An alarming 96% of those with early, asymptomatic CKD are unaware of their condition. Thus,
there is pressing need for novel strategies to combat the detrimental cycle of hypertension and kidney
damage. Importantly, Zn deficiency has been linked to impaired renal Na+ excretory function, hypertension,
and kidney damage. Notably, the renal sodium chloride cotransporter (NCC), a critical determinant of
whole-body Na+ balance and BP homeostasis in the distal convoluted tubules (DCT), has been shown to be
Zn-sensitive. Specifically, Zn-deficient mice showed upregulated NCC, enhanced Na+ reabsorption, and
elevated BP; but Zn repletion reversed these derangements. However, other reports show that, as CKD
progresses through stages, fractional urinary excretion of Zn increased as plasma levels of Zn decreased,
with a sharp increase in urinary excretion of Zn at stage 3. Critically, this is before most patients are even
diagnosed. Thus, Zn supplementation may be effective to restore BP homeostasis in early stages of CKD;
but its effects may be limited if later-stage kidney damage diminishes Zn bioavailability.
Therefore, there is an urgent need to fill the critical gaps in therapeutic knowledge of Zn supplementation
and mechanistic knowledge of the Zn-sensitive renal pathways. The overall objectives of this proposal are
to (i) assess Zn supplementation as a therapy to restore BP regulation in early and late stages of CKD, and
(ii) identify the mechanisms of Zn-sensitive DCT Na+ handling, with the ultimate goal to identify novel
therapeutic approaches effective for all stages of CKD. This will be done via these 3 Aims:
Aim 1. Assess efficacy of Zn to delay hypertension and disease progression in early CKD:
Calcineurin inhibitor-treated mice and Akita diabetic nephropathy mice will serve as CKD models to
rigorously test the novel working hypothesis that Zn supplementation in early CKD restores Zn homeostasis,
limits renal Na+ reabsorption, reduces hypertension, and slows CKD progression.
Aim 2. Assess efficacy of Zn plus a Zn ionophore to restore Zn homeostasis, renal Na+ excretion,
and BP regulation in late-stage CKD: The same mouse models at later stages will test the working
hypothesis that Zn supplementation with a Zn ionophore, promotes Zn bioavailability to overcome Zn
wasting, stimulate renal Na+ excretion, and restore BP homeostasis - despite late-stage kidney damage.
Aim 3. Establish signaling molecules underlying Zn sensitivity of DCT-dependent Na+ handling and
BP homeostasis: Developed mouse models and mouse DCT cells will be used to identify Zn-sensitive
signaling molecules that limit DCT Na+ reabsorption pathways and promote Na+ balance and BP
homeostasis.
