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Publication
Metabolic consequences of cystinuria.
Authors Woodard LE, Welch RC, Veach RA, Beckermann TM, Sha F, Weinman EJ, Ikizler TA,
Tischfield JA, Sahota A, Wilson MH
Submitted By Submitted Externally on 3/26/2020
Status Published
Journal BMC nephrology
Year 2019
Date Published 6/1/2019
Volume : Pages 20 : 227
PubMed Reference 31221135
Abstract Cystinuria is an inherited disorder of renal amino acid transport that causes
recurrent nephrolithiasis and significant morbidity in humans. It has an
incidence of 1 in 7000 worldwide making it one of the most common genetic
disorders in man. We phenotypically characterized a mouse model of cystinuria
type A resultant from knockout of Slc3a1., Knockout of Slc3a1 at RNA and protein
levels was evaluated using real-time quantitative PCR and immunofluorescence.
Slc3a1 knockout mice were placed on normal or breeder chow diets and evaluated
for cystine stone formation over time suing x-ray analysis, and the development
of kidney injury by measuring injury biomarkers. Kidney injury was also
evaluated via histologic analysis. Amino acid levels were measured in the blood
of mice using high performance liquid chromatography. Liver glutathione levels
were measured using a luminescent-based assay., We confirmed knockout of Slc3a1
at the RNA level, while Slc7a9 RNA representing the co-transporter was
preserved. As expected, we observed bladder stone formation in Slc3a1-/- mice.
Male Slc3a1-/- mice exhibited lower weights compared to Slc3a1+/+. Slc3a1-/-
mice on a regular diet demonstrated elevated blood urea nitrogen (BUN) without
elevation of serum creatinine. However, placing the knockout animals on a
breeder chow diet, containing a higher cystine concentration, resulted in the
development of elevation of both BUN and creatinine indicative of more severe
chronic kidney disease. Histological examination revealed that these dietary
effects resulted in worsened kidney tubular obstruction and interstitial
inflammation as well as worsened bladder inflammation. Cystine is a precursor
for the antioxidant molecule glutathione, so we evaluated glutathione levels in
the livers of Slc3a1-/- mice. We found significantly lowered levels of both
reduced and total glutathione in the knockout animals., Our results suggest that
that diet can affect the development and progression of chronic kidney disease
in an animal model of cystinuria, which may have important implications for
patients with this disease. Additionally, reduced glutathione may predispose
those with cystinuria to injury caused by oxidative stress. Word count: 327.




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