Renal Tubular Acidosis

Renal tubular acidosis (RTA) is a metabolic acidosis due to impaired excretion of hydrogen ion, or reabsorption of bicarbonate, or both by the kidney. These renal tubular abnormalities can occur as an inherited disease or can result from other disorders or toxins that affect the renal tubules. Disorders of bicarbonate reclamation by the proximal tubule are classified as proximal RTA, whereas disorders resulting from a primary defect in distal tubular net hydrogen secretion or from a reduced buffer trapping in the tubular lumen are called distal RTA. Hyperkalemic RTA may occur as a result of aldosterone deficiency or tubular insensitivity to its effects. The clinical classification of renal tubular acidosis has been correlated with our current physiological model of how the nephron excretes acid, and this has facilitated genetic studies that have identified mutations in several genes encoding acid and base ion transporters. Growth retardation is a consistent feature of RTA in infants. Identification and correction of acidosis are important in preventing symptoms and guide approved genetic counseling and testing.

Cloning and Expression of Sodium-Bicarbonate Cotransporter Isoform in Rat / 대한해부학회지

The potassium depletion has remarkable and opposite effect on kidney and body growth and has affected the expression of the several ion transporters. Previously, Ahn et al. have reported that HK alpha 1 and 2 subunit gene were upregulated in the hypokalemic rat kidney. To clone the unreported genes expressed in potassium deficiency, differential display PCR-based cloning strategy was used in normal and potassium-depleted rat kidney and a novel gene was isolated. Sequence analysis with blast search program identified a cDNA clone encoding an isoform of kidney sodium bicarbonate cotransporter-1. The tissue and cellular expression pattern of this gene were investigated with Northern analyses and in situ hybridization histochemistry (ISH) in normal and hypokalemic rats. This novel transcript was highly expressed in kidney and brain and at lower levels in distal colon, urinary bladder, and heart but not in salivary gland, stomach, liver, and lung in normal rat. In potassium-depleted rat, this transcript was upregulated in kidney, brain, and distal colon. By ISH, cellular distribution of this gene was highly expressed in S3 segment of proximal tubule, distal convoluted tubule, and cortical collecting duct of kidney and lower third of intestinal glands of distal colon but at lower levels in cortical and medullary thick ascending limb and medullary collecting duct of kidney and middle third of intestinal glands of distal colon. From these results, this candidate gene may play an important role in HCO3-transport by these organs during potassium depletion.

Adaptive Responses to Dexamethasone Treatment in Rat Kidney Proximal Tubules / 대한해부학회지

Excess accumulation of glucocorticoid increases acid secretion and HCO3- reabsorption in the kidney. Reabsorption of HCO3-, which almost occurs at the proximal tubule, is mediated Na+ / H+ exchanger-3 (NHE-3) and H+ -ATPase on the apical membrane and the Na + /HCO3- cotransporter-1 (NBC-1)on the basolateral membrane. Impact of glucocorticoid was investigated by immunohistochemistry and electron microscopy to correlate the changes with the effect of in vivo dexamethasone treatment for the rat kidney proximal tubule. In a control group, immunoreactivity of NHE-3 was detected in the apical membrane and the brush borders of S1, S2 and 3 segments of the proximal tubule. Immunoreactivity of NBC-1 was detected in the basolateral membrane of S1 and S2 segments of the proximal tubule. Immunoreactivity of NHE-3 and NBC-1 protein was more pronounced in dexamethasone treated groups than the control group. Dexamethasone 1 mg/kg caused most intense immunoreactivity for NHE-3 and NBC-1 protein, however, 0.01 mg/kg and 0.1 mg/kg produced less intense immunoreactivity with no appreciable differences between these lower doses of dexamethasone groups. By electron microscopy, the tubular cells of S1 segment of the control group revealed numerous mitochondria, endocytic apparatuses, lysosomes and many basal cytoplasmic processes. In dexamethasone treated groups, the cells of S1 and S2 segments of the proximal tubule had more mitochodria and more basolateral invaginations and had an increased number of more elongated microvilli, compared with the control group. The cells of the S3 segment of the control group showed scant lateral interdigitations and had a few smaller mitochondria. The cells of the S3 segment of dexamethasone treated groups had many mitochodria and an increased number of microvilli in the brush border, but revealed no difference of basolateral invaginations among the different groups of dexamethasone. These results indicate that prolonged administration of excess glucocorticoid increases NHE-3 and NBC-1 protein, and the up-regulation of these proteins could result in increased HCO3 - reabsorption in the rat renal proximal tubules. It also suggests that these adaptive responses closely correlate to morphological alterations of proximal tubular epithelial cells.

Regulations of Bicarbonate Ions in Hypokalemic Rat Kidney / 대한해부학회지

A number of acid-base or electrolyte disorders are associated with decreased or increased HCO3- reabsorption in the renal tubules. There has been a general agreement that potassium depletion induces and maintains metabolic alkalosis in rats. However, many researchers have approached such issue only from functional studies to investigate Na+/H+ exchanger (NHE-3) and Na+/HCO(3-) cotransporter (NBC) activity which closely relates to potassium depletion. In addition the results obtained vary according to their researchers. Thus the present study was employed Western blot analysis and immunohistochemistry together, to examine the alterations of expression and distribution of NHE-3 and NBC-1 with reference to HCO3- reabsorption in the kidneys of rats fed potassium free diets according to the periods. Western blot analysis demonstrated that NHE-3 protein, ~83 kDa at molecular mass, was abundantly expressed in normal group. All potassium-depleted groups showed significantly increased NHE-3 protein compared to normal group. NBC-1 protein, ~110 kDa at molecular mass, was moderately expressed in normal group. All potassium-depleted groups had much higher amounts of the protein than normal group. There was a highly increased amount of NBC-1 protein especially in K-depleted 1 week group. Immunohistochemistry showed positive immunoreactivity of NHE-3 in the apical membranes and brush borders of proximal renal tubule cells. Its reactivity was most prominent in the S3.S1 and S2 had moderate immunoreactivity. Potassium-depleted groups had an identical pattern of cellular labeling of NHE-3 protein compared with that of normal group. However the signal intensity of NHE-3 protein in potassium-depleted groups was much higher than that of normal group. Immunoreactivity of NBC-1 was observed exclusively in the basolateral plasma membranes of proximal tubule cells. There was a strong reactivity in the S1 and S2, whereas S3 did not show any reactivity. Potassium-deprived rats exhibited an identical pattern of cellular labeling of NBC-1 protein compared with that of normal rats. However, the signal intensity of NBC-1 protein was markedly increased in potassium-deprived rats. These results suggest that increased NHE-3 and NBC-1 expression resulted from potassium depletion in the renal proximal tubules, enhances HCO3-reabsorption and consequently maintains metabolic alkalosis.