Continuous Treatment with Oxalate Changes Renal Physiology and Morphology (DK0750

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DESCRIPTION (provided by applicant): The role that oxalate plays in calcium oxalate (CaOx) nephrocalcinosis and oxalate driven nephrolithiasis is not well understood. There is accruing evidence that in addition to crystal formation, oxalate promotes these conditions through its interactions with the renal epithelium, interstitium and vasculature. Differing susceptibilities to these effects may partially explain why individuals with similar risk factors have do not have similar clinical symptoms. This proposal will utilize two versions of the minipump model to study these interactions. The standard 14D protocol models moderate-to-severe hyperoxaluria in that it induces a greater than or equal to 3x increase in oxalate excretion and intratubular CaOx-nephrocalcinosis. The LongDose protocol will model the more common mild-to-moderate hyperoxaluria by inducing less than or equal to 1.5-2x increase in oxalate excretion over a 4wk period and the induction of mixed CaOx-/CaP- nephrocalcinosis. A novel aspect of this proposal is that ion chromatography and polarizing microscopy/ Yasue staining + morphometric analysis will be used to correlate oxalate's effects on specific segments of the nephron, interstitium or vasculature with intrarenal oxalate concentrations and crystal deposition. Dose response and time course studies will identify those changes which occur prior to crystal deposition and thus could be fostering nephrocalcinosis. In Specific Aim 1, the effects of 360 muM KOx/24hr for 14D on liver function, cardiomyopathy, and bone remodiling will be determined and the LongDose protocol will be developed. Specific Aim 2 will utilize RT-PCR, Northern & Western blotting and immunofluorescence to identify changes in the expression of segment specific, general distress, vasculature distress and stone disease makers during continuous, steady exposure to oxalate. Specific Aim 3 will utilize transmission electron microscopy and immunofluorescence to identify segments of the nephron and regions of the interstitium and vasculature that show morphological damage, apoptosis or proliferation during continuous, steady exposure to oxalate. Relevance to Public Health: This proposal investigates oxalate's effects on specific regions of the kidney during the early phases of CaOx- nephrocalcinosis and oxalate driven stone disease using the rat minipump model. The objective is to identify those effects which promote these conditions. Future work will determine the mechanism of these effects with the goal of developing an effective preventative therapy.