Impairment of Na/K-ATPase Signaling in Renal Proximal Tubule Contributes to Dahl Salt-sensitive Hypertension

Jiang Liu,Yanling Yan,Lijun Liu,Zijian Xie,Deepak Malhotra,Bina Joe,Joseph I Shapiro

doi:10.1074/jbc.m111.246249

Jiang Liu, Yanling Yan + Show 5 more

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https://doi.org/10.1074/jbc.m111.246249

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Abstract

We have observed that, in renal proximal tubular cells, cardiotonic steroids such as ouabain in vitro signal through Na/K-ATPase, which results in inhibition of transepithelial (22)Na(+) transport by redistributing Na/K-ATPase and NHE3. In the present study, we investigate the role of Na/K-ATPase signaling in renal sodium excretion and blood pressure regulation in vivo. In Sprague-Dawley rats, high salt diet activated c-Src and induced redistribution of Na/K-ATPase and NHE3 in renal proximal tubules. In Dahl salt sensitive (S) and resistant (R) rats given high dietary salt, we found different effects on blood pressure but, more interestingly, different effects on renal salt handling. These differences could be explained by different signaling through the proximal tubular Na/K-ATPase. Specifically, in Dahl R rats, high salt diet significantly stimulated phosphorylation of c-Src and ERK1/2, reduced Na/K-ATPase activity and NHE3 activity, and caused redistribution of Na/K-ATPase and NHE3. In contrast, these adaptations were either much less effective or not seen in the Dahl S rats. We also studied the primary culture of renal proximal tubule isolated from Dahl S and R rats fed a low salt diet. In this system, ouabain induced Na/K-ATPase/c-Src signaling and redistribution of Na/K-ATPase and NHE3 in the Dahl R rats, but not in the Dahl S rats. Our data suggested that impairment of Na/K-ATPase signaling and consequent regulation of Na/K-ATPase and NHE3 in renal proximal tubule may contribute to salt-induced hypertension in the Dahl S rat.

Highlights

Cardiotonic steroids (CTS) such as ouabain and marinobufagenin (MBG) appear to be involved in the regulation of BP and renal Naϩ handling in vivo [5,6,7] as well as the ion handling of both primary cultures and proximal tubular cell lines in vitro [7,8,9,10,11,12]
Effect of High Salt Diet on RPT Na/K-ATPase and NHE3 in Sprague-Dawley Rats—As shown in Table 1, the high salt diet significantly increased absolute urinary Naϩ excretion compared with control rats
The high salt diet decreased RPT surface contents of both transporters (Fig. 1a), and caused both transporters in RPTs to accumulate in the EE fraction (Fig. 1b)

Summary

Introduction

Cardiotonic steroids (CTS) such as ouabain and marinobufagenin (MBG) appear to be involved in the regulation of BP and renal Naϩ handling in vivo [5,6,7] as well as the ion handling of both primary cultures and proximal tubular cell lines in vitro [7,8,9,10,11,12].

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