Login to view PhD Thesis

Enter your username and password here in order to log in on the website:


Forgot your password?

Regulation of renal acid-base transporters in rats with urinary tract obstruction

Guixian Wang

Summary

1) Ureter obstruction alters expression of renal acid-base transport proteins in rat kidney.
Bilateral ureteral obstruction for 24 hours and 4 days after release of obstruction in rats was associated with markedly downregulation of a number of membrane protein transporters, which are important for renal acid-base regulation during and after release of urinary tract obstruction. This coincided with impairment in urinary net free proton excretion. In particular, NHE3 and NBC1 expression in the proximal tubules were reduced, NKCC2 in thick ascending limb and H+-ATPase expression in the collecting ducts were reduced and may contribute to renal tubular acidosis and the urinary acidification defect associated with BUO and release of BUO. Reduced expression of NBCn1 in the thick ascending limb and pendrin in the collecting duct may represent compensatory changes to the acidosis.

2) Unilateral ureteral obstruction alters expression of acid-base transporters in rat kidney
Release of unilateral ureteral obstruction in rats was associated with a manifest inadequate urinary acid excretion which is consistent with previous clinical findings. The expression of NHE3 and NBC1 was decreased in the proximal tubules, NBCn1 and NKCC2 were reduced in thick ascending limb and H+-ATPase was reduced in the collecting ducts in obstructed kidney, which may contribute to the inadequate acid secretion in response to UUO. Reduced expression pendrin in the collecting duct may represent compensatory changes to the acidosis. After 4 days of release of the obstruction there was no regulation of acid-base transporters in the contralateral non-obstructed kidney indicating compensating inability to excrete more acid.

3) Age dependent protein expression of renal acid-base transporters in rats with congenital ureter obstruction
We made the animal model of neonatal PUUO to mimic the congenital partial ureter obstruction and expected to confirm the urinary acidification defect seen in adult rats. The results demonstrated that neonatal PUUO for 7 weeks in rats were fully able to compensate in response to acid challenge. Consistent with this, the expression levels of the main acid-base transporters NHE3, NBC1, pendrin and Na+-K+-ATPase were increased in both partial obstructed and non-obstructed kidneys, whereas NBCn1 was upregulated only in contralateral non-obstructed kidneys. Longer term obstruction (14 weeks) in PUUO rats resulted in an apparent impairment of renal functions demonstrated as increased plasma creatinine and urea concentrations, plasma electrolyte imbalance, and a urinary acidification defect in response to acid loading. Consistent with reduced ability to secret acid into urine, the protein abundance of acid-base transporters NBC1, NBCn1 and Na+-K+-ATPase were significantly decreased demonstrating a time dependent development in the urinary acidification defect.
The overall conclusion of this survey is that the 3 different models of urinary tract obstruction used in the studies all are associated with reduced expression of key renal acid-base transporters located to different segments of the nephron and collecting duct. These transporters all play important roles for urinary HCO reabsorption and H+ excretion and the reduced expression observed may therefore at least in part be of pathophysiological importance for the coinciding urinary acidification defect, thereby demonstrating a functional association between the urinary excretion of protons and the molecular changes of membrane proteins in the kidney. The clinically most relevant model – partial unilateral ureteral obstruction – is associated with age/time dependent changes in downregulation of renal acid-base transporters which are associated with parallel development of a urinary acidification defect. Thus, the findings support the view that the degree, localization and duration of the obstruction are important determinants for the functional changes of the obstructed kidney.