Renal compensation to chronic hypoxic hypercapnia: downregulation of pendrin and adaptation of the proximal tubule

Abstract

December 19, 2006; doi:10.1152/ajprenal.00220.2006.-The molecular basis for the renal compensation to respiratory acidosis and specifically the role of pendrin in this condition are unclear. Therefore, we studied the adaptation of the proximal tubule and the collecting duct to respiratory acidosis. Male Wistar-Hannover rats were exposed to either hypercapnia and hypoxia [8% CO 2 and 13% O 2 (hypercapnic, n ϭ 6) or normal air (controls, n ϭ 6)] in an environmental chamber for 10 days and were killed under the same atmosphere. In hypercapnic rats, arterial pH was lower than controls (7.31 Ϯ 0.01 vs. 7.39 Ϯ 0.01, P ϭ 0.03), blood HCO 3 Ϫ concentration was increased (42 Ϯ 0.9 vs. 32 Ϯ 0.24 mM, P Ͻ 0.001), arterial PCO 2 was increased (10.76 Ϯ 0.4 vs. 7.20 Ϯ 0.4 kPa, P Ͻ 0.001), and plasma chloride concentration was decreased (92.2 Ϯ 0.7 vs. 97.2 Ϯ 0.5 mM, P Ͻ 0.001). Plasma aldosterone levels were unchanged. In the proximal tubule, immunoblotting showed an increased expression of sodium/bicarbonate exchanger protein (188 Ϯ 22 vs. 100 Ϯ 11%, P ϭ 0.005), confirmed by immunohistochemistry. Total Na/H exchanger protein expression in the cortex was unchanged by immunoblotting (119 Ϯ 10 vs. 100 Ϯ 11%, P ϭ 0.27) and immunohistochemistry. In the cortex, the abundance of pendrin was decreased (51 Ϯ 9 vs. 100 Ϯ 7%, P ϭ 0.003) by immunoblotting. Immunohistochemistry revealed that this decrease was clear in both cortical collecting ducts (CCDs) and connecting tubules (CNTs). This demonstrates that pendrin expression can be regulated in acidotic animals with no changes in aldosterone levels and no external chloride load. This reduction of pendrin expression may help in redirecting the CNT and CCD toward chloride excretion and bicarbonate reabsorption, contributing to the increased plasma bicarbonate and decreased plasma chloride of chronic respiratory acidosis.

High phenotypic intrafamilial variability in patients with Pendred syndrome and a novel duplication in the SLC26A4 gene: clinical characterization and functional studies of the mutated SLC26A4 protein

“…In the family tested in the present work, the extreme variability can not only be found in the degree of hearing impairment, but also in the time of onset for the thyroid alterations. Moreover, the evidence of a renal dysfunction in one patient is particularly interesting because this alteration in PS is seldom seen, however expected, since the SLC26A4 transporter is involved in kidney acid-base regulation and blood volume maintenance (33)(34)(35). However, no evidence exists about a direct cause-effect relationship between impaired pendrin function and kidney atrophy, and this finding could be a mere coincidence.…”

Renal β-intercalated cells maintain body fluid and electrolyte balance

“…After 3 washes, sections were incubated with a 1:1,000 dilution (in background-reducing buffer) of donkey anti-rabbit IgG coupled to Cy3 (Jackson Immunoresearch Laboratories, Inc.) in TBS, 30 minutes at room temperature, followed by 3 TBS washes. Rabbit anti-AQP2 antibodies (AQP2 H7661) were a gift from S. Frische (Aarhus University, Aarhus, Denmark) and were used by de Seigneux et al (65).…”

It Is Chloride Depletion Alkalosis, Not Contraction Alkalosis

“…Abundant evidence now supports pendrin as an important regulatory transporter in the cortical collecting ducts, which responds briskly 18 in vivo and in vitro 16 to alterations in chloride intake 19 and to acid-base perturbations including metabolic alkalosis and acidosis 20 and respiratory acidosis 21 (Table 1). The main stimuli seem to be distal chloride delivery 22 and intracellular pH.…”

“…10 Aldosterone, within its physiologic range of levels, is not important for direct pendrin regulation. 20,21 Adrenalectomized rats ingesting a low chloride diet and drinking isotonic neutral sodium phosphate excrete extremely low concentrations of chloride and maintain chloride balance. 30 Again, this suggests that chloride conservation in the distal nephron is not aldosterone dependent.…”