Kidney Week

Abstract: SA-PO608

Diet-Dependent Development of CKD in a Mouse Model of Cystinuria Type I

Session Information

• Noncystic Mendelian Diseases
  November 04, 2017 | Location: Hall H, Morial Convention Center
  Abstract Time: 10:00 AM - 10:00 AM

Category: Genetic Diseases of the Kidney

• 802 Non-Cystic Mendelian Diseases

Authors

• Woodard, Lauren Elizabeth, Tennessee Valley Healthcare System, Nashville, Tennessee, United States

Lauren Elizabeth Woodard,

• Welch, Rick C., Vanderbilt University Medical Center, Nashville, Tennessee, United States

Rick C. Welch,

• Veach, Ruth Ann, Vanderbilt University Medical Center, Nashville, Tennessee, United States

Ruth Ann Veach,

• Beckermann, Thomas M, Vanderbilt University Medical Center, Nashville, Tennessee, United States

Thomas M Beckermann,

• Sha, Feng, Vanderbilt University Medical Center, Nashville, Tennessee, United States

Feng Sha,

• Ikizler, Talat Alp, Tennessee Valley Healthcare System, Nashville, Tennessee, United States

Talat Alp Ikizler,

• Tischfield, Jay A., Rutgers University, Piscataway, New Jersey, United States

Jay A. Tischfield,

• Sahota, Amrik, Rutgers University, Piscataway, New Jersey, United States

Amrik Sahota,

• Wilson, Matthew H., Tennessee Valley Healthcare System, Nashville, Tennessee, United States

Matthew H. Wilson,

Background

Cystinuria type I results from mutation of SLC3A1 and is a disorder of renal amino acid transport, resulting in recurrent nephrolithiasis and significant morbidity. It is one of the most common autosomal recessive genetic disorders in humans with an incidence in the United States of 1 in 15000. Using two diets, we compared the rate of stone and chronic kidney development in Slc3a1 knockout mice.

Methods

In a mouse model of cystinuria type I, mice lacking the gene had increased basic amino acids in their urine and developed cystine stones. Mice were supplied with either a normal or breeder chow diet and allowed to age for approximately one year. Blood and tissue samples were obtained to assess development of chronic kidney disease in each group. We also evaluated cystine levels in the blood and glutathione (GSH) levels in the liver.

Results

When placed on a normal diet, aged Slc3a1 knockout mice had an elevated blood urea nitrogen (BUN) and normal serum creatinine. Slc3a1 knockout mice that were aged on a breeder diet containing higher levels of cystine had more severe chronic kidney disease as indicated by both elevated BUN and serum creatinine. Histologic analysis also revealed a greater degree of kidney and bladder injury in aged mice maintained on a breeder diet than in those maintained on a normal diet. Additionally, we observed lower levels of cystine in the blood of knockout animals. The availability of cysteine, which forms cystine when two molecules are joined together, is a major determinant of the regulation of GSH synthesis. We found that glutathione levels in the liver were reduced in the Slc3a1 knockout animals.

Conclusion

These results suggest that diet can modulate the severity of kidney disease that developed over time in an animal model of cystinuria and may have implications for the potential to modulate disease severity in cystinuric patients. Additionally, lack of Slc3a1 function results in lower blood cystine and tissue glutathione levels indicating a metabolic phenotype beyond just kidney stone formation in cystinuria.

Funding

• NIDDK Support