Distal renal tubular acidosis in mice that lack the forkhead transcription factor Foxi1.
While macro- and microscopic kidney development appear to proceed normally in mice that lack Foxi1, electron microscopy reveals an altered ultrastructure of cells lining the distal nephron. Northern blot analyses, cRNA in situ hybridizations, and immunohistochemistry demonstrate a complete loss of expression of several anion transporters, proton pumps, and anion exchange proteins expressed by intercalated cells of the collecting ducts, many of which have been implicated in hereditary forms of distal renal tubular acidosis (dRTA). In Foxi1-null mutants the normal epithelium with its two major cell types - principal and intercalated cells - has been replaced by a single cell type positive for both principal and intercalated cell markers. To test the functional consequences of these alterations, Foxi1(-/-) mice were compared with WT littermates in their response to an acidic load. This revealed an inability to acidify the urine as well as a lowered systemic buffer capacity and overt acidosis in null mutants. Thus, Foxi1(-/-) mice seem to develop dRTA due to altered cellular composition of the distal nephron epithelium, thereby denying this epithelium the proper gene expression pattern needed for maintaining adequate acid-base homeostasis.
Blomqvist
Sandra Rodrigo
SR
Medical Genetics, Department of Medical Biochemistry, Institute of Anatomy and Cell Biology, Göteborg University, Sweden.
Vidarsson
Hilmar
H
Fitzgerald
Sharyn
S
Johansson
Bengt R
BR
Ollerstam
Anna
A
Brown
Russell
R
Persson
A Erik G
AE
Bergström G
G öran
Gö
Enerbäck
Sven
S
D000141:Acidosis, Renal Tubular / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D015152:Blotting, Northern; D004268:DNA-Binding Proteins / Q000172:deficiency* / Q000235:genetics; D004848:Epithelium / Q000473:pathology / Q000648:ultrastructure; D051858:Forkhead Transcription Factors; D007668:Kidney / Q000473:pathology; D051379:Mice; D018613:Microscopy, Confocal; D015534:Trans-Activators / Q000172:deficiency* / Q000235:genetics
D004268:DNA-Binding Proteins; C477894:FOXI1 protein, human; D051858:Forkhead Transcription Factors; D015534:Trans-Activators