The proximal tubule reabsorbs 80% of the filtered bicarbonate in adult animals. The transporters responsible for apical proton secretion and basolateral bicarbonate transport have been characterized and are limited to their respective membranes for efficient vectorial bicarbonate transport. Acid-base changes can affect the rate of proximal tubule bicarbonate absorption, and chronic changes can produce an intrinsic adaptation in transporter activity. However, little is known about the mechanisms of acidification, the rate of transporter activity and the regulation of acidification in the developing proximal tubule. Nephrogenesis is still occurring in newborn infants born before 36 weeks gestation. These infants often develop metabolic and respiratory acidosis. It is known that immature proximal tubules transport fluid and bicarbonate at a fraction of the adult rate. However, it is unknown whether immature proximal tubules are functioning at maximal capacity or if an adaptive augmentation in transport is possible. The ability of the kidney to adapt to acute and chronic acid-base changes affects the ability of the organism to respond to and survive these environmental stresses. With the increased survivorship of very premature infants, the ability of the kidney to adapt to metabolic and respiratory acidosis is of great clinical importance.
The first aim of this proposal is to use in vitro microperfusion and measurements of intracellular pH to examine how differentiation of the proximal tubule from the primitive renal vesicle to the mature tubular segment affects the localization and activity of transporters responsible for acidification.
The second aim i s to examine if acute changes in peritubular pH, pCO2 and HCO3 as well as changes in peritubular physical factors in vitro can modulate acidification in the immature proximal tubule. Finally, I will examine if the intrinsic rate of development and maturation of proximal tubular acidification can be altered by imposing environmental stresses on newborn rabbits which frequently affect premature infants.
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