Increased renal proximal convoluted tubule transport contributes to hypertension in Cyp4a14 knockout mice

Abstract

Background/aims: Disrupting the enzyme Cyp4a14 in mice leads to hypertension, which is more severe in the male mice and appears to be due to androgen excess. Because the Cyp4a14 enzyme is located in the proximal tubule of the kidney, we hypothesized that there could be dysregulation of transport in this segment that could contribute to the hypertension.

Methods: Wild-type (SV/129) mice and mice that had targeted disruption of the Cyp4a14 gene were studied. Proximal convoluted tubules (PCT) from knockout and wild-type mice were dissected and perfused in vitrofor measurement of volume absorption (J(V)). Expression of the sodium-hydrogen exchanger 3 (NHE3), the predominant transporter responsible for sodium transport in this segment, was measured by immunoblot. Renal vascular (afferent arteriole) responses to angiotensin and endothelin were also measured.

Results: PCT volume absorption was elevated in tubules from the Cyp4a14 knockout mice as compared to the wild-type mice. Brush border membrane NHE3 expression was almost 2-fold higher in Cyp4a14 knockout mice than in wild-type mice. No difference was found in the afferent arteriolar response.

Conclusion: Thus, hypertension in the Cyp4a14 knockout mice appears to be driven by excessive fluid reabsorption in the proximal tubule, which is secondary to overexpression of NHE3.

Fig. 1.

The volume absorption rates of PCT from wild-type (SV/129) mice and Cyp4a14 KO mice. Volume absorption was significantly higher in the Cyp4a14 KO mice than in the wild-type control mice (∗ p < 0.05).

Fig. 2.

Immunoblots of the brush border membrane NHE3 expression. The apical membranes of the proximal tubules from Cyp4a14 KO mice have a higher expression of NHE3 than the wild-type control mice.

Fig. 3.

Vasoconstrictor response of the afferent arteriole to angiotensin II and endothelin. As can be seen, there was no difference in the vascular response to these 2 vasoconstrictors.