Subscribe Now Subscribe Today
Abstract
Fulltext PDF
References
Research Article
 
Mutation of ATP6V0A4 Gene Leads to Acid-base Disturbance and Inferred in Kidney Stone Formation



Lizhong Han, Mingming Li, Hao Wang, Guanjun Lu and Peijun Li
 
ABSTRACT

Background and Objective: The mutation in the V-type proton ATPase enzyme is encoded by the ATP6V0A4 gene and it leads to renal tubular acidosis associated with preserved hearing. Both in mice and human, the B1 and A4 subunit are the two important subunits which play a major role. The mutation of B1 subunit of heterozygous carriers in human leads to incomplete dRTA and calcium deposits (kidney stone) in humans. Therefore, the present study aimed to investigate the development of acid-base disturbances in ATP6V0A4 gene mutation in mice during a seven-day acid-load. Materials and Methods: In this investigation ATP6V0A4+/+ (wildtype), ATP6V0A4+/- (heterozygous) and ATP6V0A4-/- (homozygous) mice were subjected to 7 days acid-load and the metabolic and biochemical changes were monitored and analyzed to observe the acid-base balance, kidney function and protein expression. Results: The study observed that ATP6V0A4-/- mice tend to have a high level of alkali urine and low concentration of NH4 level. On the other hand, the ATP6V0A4+/- mice observed no significant difference in the biochemical parameters for urine analysis. But the heterozygous (+/-) mice observed a higher level of Cl and pCO2. The study observed that ATP6V0A4+/+ and ATP6V0A4+/- mice had localized intercalated cells in the B1 subunit. However, the expression of B1 and A4 subunit gradually decreased in the ATP6V0A4+/+ renal membrane. There were the reduction in the B1 subunit in the ATP6V0A4-/- and the ablation of B1 subunit was observed in the collecting duct of the ATP6V0A4-/- mice. Conclusion: To conclude, the study observed that ATP6V0A4+/- mice developed a mild distal-RTA which is compensated by respiration and in the absence of the B1 subunit for the compensatory mechanism occurs inside the collecting duct of ATP6V0A4-/- mice kidneys.

Services
Related Articles in ASCI
Similar Articles in this Journal
Search in Google Scholar
View Citation
Report Citation

 
Received: October 30, 2018; Accepted: November 22, 2018; Published: February 13, 2019

REFERENCES
Blomqvist, S.R., H. Vidarsson, S. Fitzgerald, B.R. Johansson and A. Ollerstam et al., 2004. Distal renal tubular acidosis in mice that lack the forkhead transcription factor Foxi1. J. Clin. Invest., 113: 1560-1570.
Direct Link  |  

Bourgeois, S., C. Bettoni, S. Baron and C.A. Wagner, 2018. Haploinsufficiency of the mouse Atp6v1b1 gene leads to a mild acid-base disturbance with implications for kidney stone disease. Cell. Physiol. Biochem., 47: 1095-1107.
CrossRef  |  Direct Link  |  

Buckalew, Jr., V.M., 1989. Nephrolithiasis in renal tubular acidosis. J. Urol., 141: 731-737.
CrossRef  |  Direct Link  |  

Christensen, H.L., T.G. Paunescu, V. Matchkov, D. Barbuskaite, D. Brown, H.H. Damkier and J. Praetorius, 2017. The V‐ATPase is expressed in the choroid plexus and mediates cAMP‐induced intracellular pH alterations. Physiol. Rep., Vol. 5. 10.14814/phy2.13072

Cotter, K., L. Stransky, C. McGuire and M. Forgac, 2015. Recent insights into the structure, regulation and function of the V-ATPases. Trends Biochem. Sci., 40: 611-622.
CrossRef  |  Direct Link  |  

Dhayat, N.A., A. Schaller, G. Albano, J. Poindexter and C. Griffith et al., 2016. The vacuolar H+-ATPase B1 subunit polymorphism p. E161K associates with impaired urinary acidification in recurrent stone formers. J. Am. Soc. Nephrol., 27: 1544-1554.
CrossRef  |  Direct Link  |  

Escobar, L.I., C. Simian, C. Treard, D. Hayek and C. Salvador et al., 2016. Mutations in ATP6V1B1 and ATP6V0A4 genes cause recessive distal renal tubular acidosis in Mexican families. Mol. Genet. Genomic Med., 4: 303-311.
CrossRef  |  Direct Link  |  

Esmail, S., N. Kartner, Y. Yao, J.W. Kim, R.A. Reithmeier and M.F. Manolson, 2018. N‐linked glycosylation of a subunit isoforms is critical for vertebrate vacuolar H+‐ATPase (V‐ATPase) biosynthesis. J. Cell. Biochem., 119: 861-875.
CrossRef  |  Direct Link  |  

Feldman, M., M. Prikis, Y. Athanasiou, A. Elia, A. Pierides and C.C. Deltas, 2006. Molecular investigation and long-term clinical progress in Greek Cypriot families with recessive distal renal tubular acidosis and sensorineural deafness due to mutations in the ATP6V1B1 gene. Clin. Genet., 69: 135-144.
CrossRef  |  Direct Link  |  

Frische, S., R. Chambrey, F. Trepiccione, R. Zamani and N. Marcussen et al., 2018. H+-ATPase B1 subunit localizes to thick ascending limb and distal convoluted tubule of rodent and human kidney. Am. J. Physiol. Renal Physiol., 315: F429-F444.
PubMed  |  Direct Link  |  

Fuster, D.G., J. Zhang, X.S. Xie and O.W. Moe, 2008. The vacuolar-ATPase B1 subunit in distal tubular acidosis: Novel mutations and mechanisms for dysfunction. Kidney Int., 73: 1151-1158.
CrossRef  |  Direct Link  |  

Gomez, J., H. Gil-Pena, F. Santos, E. Coto and A. Arango et al., 2018. Primary distal renal tubular acidosis: Novel findings in patients studied by next-generation sequencing. Pediatr. Res., Vol. 3.

Hill, L.L., 1990. Body composition, normal electrolyte concentrations and the maintenance of normal volume, tonicity and acid-base metabolism. Pediat. Clin. N. Am., 37: 241-256.
CrossRef  |  Direct Link  |  

Hoppe, B. and M.J. Kemper, 2010. Diagnostic examination of the child with urolithiasis or nephrocalcinosis. Pediat. Nephrol., 25: 403-413.
CrossRef  |  Direct Link  |  

Imai, E., S. Kaneko, T. Mori, T. Okado, S. Uchida and Y. Tsukamoto, 2016. A novel heterozygous mutation in the ATP6V0A4 gene encoding the V-ATPase a4 subunit in an adult patient with incomplete distal renal tubular acidosis. Clin. Kidney J., 9: 424-428.
CrossRef  |  Direct Link  |  

Jorgensen, K., 1957. Titrimetric determination of the net excretion of acid/base in urine. Scand. J. Clin. Lab. Investi., 9: 287-291.
CrossRef  |  Direct Link  |  

Laing, C.M., A.M. Toye, G. Capasso and R.J. Unwin, 2005. Renal tubular acidosis: Developments in our understanding of the molecular basis. Int. J. Biochem. Cell Biol., 37: 1151-1161.
CrossRef  |  Direct Link  |  

Lowry, O.H., N.J. Rosebrough, A.L. Farr and R.J. Randall, 1951. Protein measurement with the folin phenol reagent. J. Biol. Chem., 193: 265-275.
PubMed  |  Direct Link  |  

Mohebbi, N., R. Vargas‐Poussou, S.C.A. Hegemann, B. Schuknecht, A.D. Kistler, R.P. Wuthrich and C.A. Wagner, 2013. Homozygous and compound heterozygous mutations in the ATP6V1B1 gene in patients with renal tubular acidosis and sensorineural hearing loss. Clin. Genet., 83: 274-278.
CrossRef  |  Direct Link  |  

Norgett, E.E., Z.J. Golder, B. Lorente-Canovas, N. Ingham, K.P. Steel and F.E.K. Frankl, 2012. Atp6v0a4 knockout mouse is a model of distal renal tubular acidosis with hearing loss, with additional extrarenal phenotype. Proc. Nat. Acad. Sci., 109: 13775-13780.
CrossRef  |  Direct Link  |  

Palazzo, V., A. Provenzano, F. Becherucci, G. Sansavini and B. Mazzinghi et al., 2017. The genetic and clinical spectrum of a large cohort of patients with distal renal tubular acidosis. Kidney Int., 91: 1443-1255.
CrossRef  |  Direct Link  |  

Perez-Sayans, M., J.M. Somoza-Martin, F. Barros-Angueira, J.M.G. Rey and A. Garcia-Garcia, 2009. V-ATPase inhibitors and implication in cancer treatment. Cancer Treat. Rev., 35: 707-713.
CrossRef  |  Direct Link  |  

Trepiccione, F., S.D. Gerber, F. Grahammer, K.I. Lopez-Cayuqueo and V. Baudrie et al., 2016. Renal Atp6ap2/(Pro) renin receptor is required for normal vacuolar H+-ATPase function but not for the renin-angiotensin system. J. Am. Soc. Nephrol., 27: 3320-3330.
CrossRef  |  Direct Link  |  

Vasudevan, V., P. Samson, A.D. Smith and Z. Okeke, 2017. The genetic framework for development of nephrolithiasis. Asian J. Urol., 4: 18-26.
CrossRef  |  Direct Link  |  

Weiner, I.D. and J.W. Verlander, 2017. Ammonia transporters and their role in acid-base balance. Phys. Rev., 97: 465-494.
CrossRef  |  Direct Link  |  

Zhang, C., H. Ren, P. Shen, Y. Xu and W. Zhang et al., 2015. Clinical evaluation of Chinese patients with primary distal renal tubular acidosis. Internal Med., 54: 725-730.
CrossRef  |  Direct Link  |  

©  2019 Science Alert. All Rights Reserved
Fulltext PDF References Abstract