Deafness and renal tubular acidosis in mice lacking the K-Cl co-transporter Kcc4

Abstract

Hearing depends on a high K+ concentration bathing the apical membranes of sensory hair cells. K+ that has entered hair cells through apical mechanosensitive channels is transported to the stria vascularis for re-secretion into the scala media1. K+ probably exits outer hair cells by KCNQ4 K+ channels2,3, and is then transported—by means of a gap junction system connecting supporting Deiters' cells and fibrocytes4—back to the stria vascularis. We show here that mice lacking the K+/Cl- (K-Cl) co-transporter Kcc4 (coded for by Slc12a7) are deaf because their hair cells degenerate rapidly after the beginning of hearing. In the mature organ of Corti, Kcc4 is restricted to supporting cells of outer and inner hair cells. Our data suggest that Kcc4 is important for K+ recycling1,5 by siphoning K+ ions after their exit from outer hair cells into supporting Deiters’ cells, where K+ enters the gap junction pathway. Similar to some human genetic syndromes6, deafness in Kcc4-deficient mice is associated with renal tubular acidosis. It probably results from an impairment of Cl- recycling across the basolateral membrane of acid-secreting α-intercalated cells of the distal nephron.

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Figure 1: Hearing loss of Kcc4-/- mice.
Figure 2: Inner ear morphology by haematoxylin/eosin staining.
Figure 3: Kcc4 in the cochlea.
Figure 4: Kcc4 in the kidney.

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Acknowledgements

We thank J. Faulhaber and H. Ehmke for blood gas analysis; M. Bösl for blastocyst injection and implantation; M. Knipper for the prestin antiserum; M. Knepper for the aquaporin 2 antiserum; S. Gluck for the proton ATPase antiserum; M. Kolster, B. Dierkes and I. Öztürk for technical assistance; H. Voss for taking care of animals; and U. Koch for support. This work was supported by grants from the Deutsche Forschungsgemeinschaft, the Fonds der Chemischen Industrie, and the Prix Louis-Jeantet de Médecine to T.J.J.

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Correspondence to Thomas J. Jentsch.

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