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 #
5R01DK041612-18
Application #
8441619
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
2013-04-01
Budget End
2014-03-31
Support Year
18
Fiscal Year
2013
Total Cost
$290,668
Indirect Cost
$105,529
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
Baum, Michel (2016) Luminal angiotensin II stimulates rat medullary thick ascending limb chloride transport in the presence of basolateral norepinephrine. Am J Physiol Renal Physiol 310:F294-9
Baum, Michel (2016) Neonatal nephrology. Curr Opin Pediatr 28:170-2
Cheng, Chih-Jen; Yoon, Joonho; Baum, Michel et al. (2015) STE20/SPS1-related proline/alanine-rich kinase (SPAK) is critical for sodium reabsorption in isolated, perfused thick ascending limb. Am J Physiol Renal Physiol 308:F437-43
Gattineni, Jyothsna; Baum, Michel (2015) Developmental changes in renal tubular transport-an overview. Pediatr Nephrol 30:2085-98
Babich, Victor; Di Sole, Francesca (2015) The Na+/H+ Exchanger-3 (NHE3) Activity Requires Ezrin Binding to Phosphoinositide and Its Phosphorylation. PLoS One 10:e0129306
Gleason, Catherine E; Frindt, Gustavo; Cheng, Chih-Jen et al. (2015) mTORC2 regulates renal tubule sodium uptake by promoting ENaC activity. J Clin Invest 125:117-28
Wu, Yipin; Baum, Michel; Huang, Chou-Long et al. (2015) Two inwardly rectifying potassium channels, Irk1 and Irk2, play redundant roles in Drosophila renal tubule function. Am J Physiol Regul Integr Comp Physiol 309:R747-56
Lozano, German; Elmaghrabi, Ayah; Salley, Jordan et al. (2015) Effect of prenatal programming and postnatal rearing on glomerular filtration rate in adult rats. Am J Physiol Renal Physiol 308:F411-9
Pirojsakul, Kwanchai; Gattineni, Jyothsna; Dwarakanath, Vangipuram et al. (2015) Renal NHE expression and activity in neonatal NHE3- and NHE8-null mice. Am J Physiol Renal Physiol 308:F31-8
Babich, Victor; Vadnagara, Komal; Di Sole, Francesca (2015) Dual Effect of Adenosine A1 Receptor Activation on Renal O2 Consumption. J Cell Physiol 230:3093-104

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