Metabolic consequences of cystinuria
Abstract Background 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 mou...
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| Format: | Article |
| Language: | English |
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BMC
2019-06-01
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| Series: | BMC Nephrology |
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| Online Access: | http://link.springer.com/article/10.1186/s12882-019-1417-8 |
| _version_ | 1818029996881477632 |
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| author | Lauren E. Woodard Richard C. Welch Ruth Ann Veach Thomas M. Beckermann Feng Sha Edward J. Weinman Talat Alp Ikizler Jay A. Tischfield Amrik Sahota Matthew H. Wilson |
| author_facet | Lauren E. Woodard Richard C. Welch Ruth Ann Veach Thomas M. Beckermann Feng Sha Edward J. Weinman Talat Alp Ikizler Jay A. Tischfield Amrik Sahota Matthew H. Wilson |
| author_sort | Lauren E. Woodard |
| collection | DOAJ |
| description | Abstract Background 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. Methods 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. Results 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. Conclusions 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. |
| first_indexed | 2024-12-10T05:28:34Z |
| format | Article |
| id | doaj.art-34f494f6358f467691d7f610d71a6800 |
| institution | Directory Open Access Journal |
| issn | 1471-2369 |
| language | English |
| last_indexed | 2024-12-10T05:28:34Z |
| publishDate | 2019-06-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Nephrology |
| spelling | doaj.art-34f494f6358f467691d7f610d71a68002022-12-22T02:00:37ZengBMCBMC Nephrology1471-23692019-06-012011910.1186/s12882-019-1417-8Metabolic consequences of cystinuriaLauren E. Woodard0Richard C. Welch1Ruth Ann Veach2Thomas M. Beckermann3Feng Sha4Edward J. Weinman5Talat Alp Ikizler6Jay A. Tischfield7Amrik Sahota8Matthew H. Wilson9Department of Veterans Affairs, Tennessee Valley Healthcare SystemDivision of Nephrology and Hypertension, Department of Medicine, Vanderbilt University Medical CenterDivision of Nephrology and Hypertension, Department of Medicine, Vanderbilt University Medical CenterDivision of Nephrology and Hypertension, Department of Medicine, Vanderbilt University Medical CenterDivision of Nephrology and Hypertension, Department of Medicine, Vanderbilt University Medical CenterDepartment of Veterans Affairs, Michael E. DeBakey VA Medical CenterDepartment of Veterans Affairs, Tennessee Valley Healthcare SystemDepartment of Genetics, Rutgers UniversityDepartment of Genetics, Rutgers UniversityDepartment of Veterans Affairs, Tennessee Valley Healthcare SystemAbstract Background 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. Methods 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. Results 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. Conclusions 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.http://link.springer.com/article/10.1186/s12882-019-1417-8CystinuriaCystineChronic kidney diseaseKidney stonesNephrolithiasis |
| spellingShingle | Lauren E. Woodard Richard C. Welch Ruth Ann Veach Thomas M. Beckermann Feng Sha Edward J. Weinman Talat Alp Ikizler Jay A. Tischfield Amrik Sahota Matthew H. Wilson Metabolic consequences of cystinuria BMC Nephrology Cystinuria Cystine Chronic kidney disease Kidney stones Nephrolithiasis |
| title | Metabolic consequences of cystinuria |
| title_full | Metabolic consequences of cystinuria |
| title_fullStr | Metabolic consequences of cystinuria |
| title_full_unstemmed | Metabolic consequences of cystinuria |
| title_short | Metabolic consequences of cystinuria |
| title_sort | metabolic consequences of cystinuria |
| topic | Cystinuria Cystine Chronic kidney disease Kidney stones Nephrolithiasis |
| url | http://link.springer.com/article/10.1186/s12882-019-1417-8 |
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