Neonates are more prone to fluid and electrolyte disorders than adults due, in part, to the immature kidney. We have shown that there are marked differences between the rate and characteristics of neonatal proximal tubule NaCl and NaHCO3 transport than that in the adult. Proximal tubule reabsorption of NaCl and NaHCO3 is dependent in large part on the luminal Na+/H+ exchanger, which in adults is NHE3. Neonates have almost no apical membrane NHE3 despite having a significant amount of Na+/H+ exchanger activity. We provide evidence that the neonate has a different Na+/H+ isoform than the adult. We show that the brush border membrane of the neonatal proximal tubule expresses abundant NHE8 and little NHE3, compared to the adult that primarily expresses NHE3 and little NHE8. However, we know very little about the functional characteristics NHE8, its regulation and what causes the isoform switch during postnatal development to NHE3.
The aims of this proposal are to characterize the function of NHE8 in vitro and in vivo. We will use a highly sensitive technique of pH selective electrodes on the whole-cell patch configuration where we have total control of the extra and intracellular milieu to characterize the function of NHE8. We will examine the factors responsible for the isoform switch from NHE8 during postnatal development using a novel animal model to study renal development, the adrenalectomized-hypothyroid rat, where the maturation of proximal tubule Na+/H+ exchange and NHE3 is nearly arrested at the neonatal level. We have shown that NHE3 levels are increased by the glucocorticoids and thyroid hormone. The adrenalectomized-hypothyroid rat will allow us to test the hypothesis that the relative hypothyroid, glucocorticoid deficient state of the neonate prevents the expression of NHE3 making another isoform with different regulatory properties necessary for neonatal proximal tubule acidification. We will examine if NHE8 is regulated in the opposite direction by glucocorticoids and thyroid hormone resulting in down regulation in the adult. Finally, we now have a NHE8 null mouse that will allow us to examine the relative functional importance of this developmental NHE isoform in renal acidification and its relative importance in response to acidosis in both neonates and adults.

Public Health Relevance

Neonates are more prone to develop acidosis and volume depletion from diseases such as diarrhea that can be life threatening. This susceptibility to acidosis is in large part due to the fact that the newborn kidney is less well developed and in some cases uses different transport proteins for electrolyte transport than adults. This proposal will characterize a neonatal transporter that likely plays an important role in neonatal kidney acidification and salt transport.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK041612-17
Application #
8246527
Study Section
Cellular and Molecular Biology of the Kidney Study Section (CMBK)
Program Officer
Hoshizaki, Deborah K
Project Start
1991-02-01
Project End
2014-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
17
Fiscal Year
2012
Total Cost
$301,211
Indirect Cost
$109,357
Name
University of Texas Sw Medical Center Dallas
Department
Pediatrics
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
Gattineni, Jyothsna; Baum, Michel (2015) Developmental changes in renal tubular transport-an overview. Pediatr Nephrol 30:2085-98
Gattineni, Jyothsna; Alphonse, Priyatharshini; Zhang, Qiuyu et al. (2014) Regulation of renal phosphate transport by FGF23 is mediated by FGFR1 and FGFR4. Am J Physiol Renal Physiol 306:F351-8
Baum, Michel (2014) The bone kidney axis. Curr Opin Pediatr 26:177-9
Siddique, Khurrum; Guzman, German Lozano; Gattineni, Jyothsna et al. (2014) Effect of postnatal maternal protein intake on prenatal programming of hypertension. Reprod Sci 21:1499-507
Bobulescu, Ion Alexandru; Lotan, Yair; Zhang, Jianning et al. (2014) Triglycerides in the human kidney cortex: relationship with body size. PLoS One 9:e101285
Mizuno, Masaki; Lozano, German; Siddique, Khurrum et al. (2014) Enalapril attenuates the exaggerated sympathetic response to physical stress in prenatally programmed hypertensive rats. Hypertension 63:324-9
Mizuno, Masaki; Siddique, Khurrum; Baum, Michel et al. (2013) Prenatal programming of hypertension induces sympathetic overactivity in response to physical stress. Hypertension 61:180-6
Cheng, Chih-Jen; Baum, Michel; Huang, Chou-Long (2013) Kidney-specific WNK1 regulates sodium reabsorption and potassium secretion in mouse cortical collecting duct. Am J Physiol Renal Physiol 304:F397-402
Bobulescu, I Alexandru; Maalouf, Naim M; Capolongo, Giovanna et al. (2013) Renal ammonium excretion after an acute acid load: blunted response in uric acid stone formers but not in patients with type 2 diabetes. Am J Physiol Renal Physiol 305:F1498-503
Babich, Victor; Vadnagara, Komal; Di Sole, Francesca (2013) The biophysical and molecular basis of intracellular pH sensing by Na+/H+ exchanger-3. FASEB J 27:4646-58

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