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1 Medicine, University of Texas Medical Branch, Galveston, Texas, USA
* To whom correspondence should be addressed. E-mail: dgood{at}utmb.edu.
Recently we demonstrated that aldosterone inhibits HCO3- absorption in the rat medullary thick ascending limb (MTAL) via a nongenomic pathway blocked by inhibitors of ERK activation. Here we examined the effects on the MTAL of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), which regulates cell functions through nongenomic mechanisms in nonrenal systems. Addition of 1 nM 1,25(OH)2D3 to the bath decreased HCO3- absorption by 24%, from 15.0 ± 0.3 to 11.4 ± 0.5 pmol/min/mm(P<0.001). This inhibition was maximal within 60 min and was eliminated by pretreatment with actinomycin D, cycloheximide, or inhibitors of protein kinase C. In MTAL bathed with 1 nM aldosterone (added 15-20 min before 1,25(OH)2D3), both the absolute (5.6 ± 0.3 vs 3.6 ± 0.3 pmol/min/mm) and fractional (49 ± 2 vs 24 ± 2%) decreases in HCO3- absorption induced by 1,25(OH)2D3 were significantly greater than those in the absence of aldosterone (P<0.05). The effect of aldosterone to potentiate inhibition by 1,25(OH)2D3 was not affected by spironolactone but was eliminated by the MEK/ERK inhibitor U0126. U0126 did not affect inhibition of HCO3- absorption by 1,25(OH)2D3 alone. Aldosterone induced rapid activation of ERK via a transcription-independent pathway. We conclude: 1) 1,25(OH)2D3 inhibits HCO3- absorption in the MTAL via a genomic pathway involving PKC, which may contribute to 1,25(OH)2D3-induced regulation of urinary net acid and/or Ca2+ excretion; 2) aldosterone potentiates inhibition by 1,25(OH)2D3 through an ERK-dependent, nongenomic pathway. These results identify a novel regulatory interaction whereby aldosterone acts via nongenomic mechanisms to enhance the genomic response to 1,25(OH)2D3. Aldosterone may influence a broad range of biological processes, including epithelial transport, by modifying the response of target tissues to 1,25(OH)2D3 stimulation.
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