Oxalate-Induced Renal Scarring and Crystal Retention

Project: Research project

Project Details


DESCRIPTION (provided by applicant): Renal manifestations of hyperoxaluria
include nephrolithiasis and, when extreme, interstitial scarring and loss of
kidney function. Although primary hyperoxaluria is relatively rare,
hyperoxaluria secondary to gastrointestinal malabsorption is not, and in both
disease states oxalate-induced nephrolithiasis, nephrocalcinosis, and renal
scarring can cause renal failure and death. Furthermore, calcium oxalate kidney
stone formation is extremely common in the general population, and evidence
suggests that minimal, perhaps transient elevations in urinary oxalate
concentration may be an important risk factor in many. Since the cellular
effect of oxalate appears to depend critically on the concentration, in
Specific Aim #1 we propose development of a sustained and constant model of
hyperoxalemia and hyperoxaluria that utilizes an osmotic microinfusion pump.
The plasma oxalate will be clamped, and the resulting oxalate concentration in
the cortex, medulla, and final urine will be determined. In addition, we will
measure the resulting effects on renal function, urinary markers of cellular
injury and oxidative stress, and histologically examine kidneys that have been
exposed to these defined concentrations of oxalate, in order to correlate
cellular changes with the local oxalate concentrations. Since the effect of
oxalate is also critically dependent on cell type, in Specific Aim #2 a tissue
culture model system will be employed to precisely define conditions under
which oxalate induces oxidative stress in proximally-, distally-, and
interstitially-derived cells, and determine the pathways employed. In Specific
Aim #3 we will identify cellular responses to injury, including that caused by
oxalate, that might enhance crystal retention in the kidney. By integrating
these 3 specific aims the most physiologically relevant cellular responses will
be determined by carefully correlating the plasma and urine oxalate
concentrations, the local oxalate concentrations to which renal cells are
exposed in vivo, and the cellular responses to oxalate. A key feature of this
grant is the inclusion of 2 investigators new to oxalosis and nephrolithiasis
research. Dr. Eddie Greene will bring extensive experience from his studies of
the cellular effects of oxidative stress in order to define the mechanisms
whereby oxalate triggers cellular signaling pathways in renal cells. Dr. Luis
Juncos has extensive experience studying the regulation of renal blood flow in
vivo, and will be critical in our efforts to develop the constant infusion
model of hyperoxalemia and hyperoxaluria.
StatusNot started


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