Inhibition of Mitochondrial Complex-1 Prevents the Downregulation of NKCC2 and ENaCα in Obstructive Kidney Disease.

Yue Zhang,Yue Zhang,Zhanjun Jia,Zhanjun Jia,Ying Sun,Ying Sun,Songming Huang,Songming Huang,Aihua Zhang,Aihua Zhang,Guixia Ding

doi:10.1038/srep12480

Yue Zhang, Yue Zhang + Show 9 more

Open Access

https://doi.org/10.1038/srep12480

Copy DOI

Abstract

Ureteral obstruction with subsequent hydronephrosis is a common clinical complication. Downregulation of renal sodium transporters in obstructed kidneys could contribute to impaired urinary concentrating capability and salt waste following the release of a ureteral obstruction. The current study was undertaken to investigate the role of mitochondrial complex-1 inhibition in modulating sodium transporters in obstructive kidney disease. Following unilateral ureteral obstruction (UUO) for 7 days, a global reduction of sodium transporters, including NHE3, α-Na-K-ATPase, NCC, NKCC2, p-NKCC2, ENaCα, and ENaCγ, was observed, as determined via qRT-PCR and/or Western blotting. Interestingly, inhibition of mitochondrial complex-1 by rotenone markedly reversed the downregulation of NKCC2, p-NKCC2, and ENaCα. In contrast, other sodium transporters were not affected by rotenone. To study the potential mechanisms involved in mediating the effects of rotenone on sodium transporters, we examined a number of known sodium modulators, including PGE2, ET1, Ang II, natriuretic peptides (ANP, BNP, and CNP), and nitric oxide synthases (iNOS, nNOS, and eNOS). Importantly, among these modulators, only BNP and iNOS were significantly reduced by rotenone treatment. Collectively, these findings demonstrated a substantial role of mitochondrial dysfunction in mediating the downregulation of NKCC2 and ENaCα in obstructive kidney disease, possibly via iNOS-derived nitric oxide and BNP.

Highlights

Obstructive kidney disease is a common clinical complication[1,2,3,4]
To study the role of rotenone treatment in the regulation of sodium transporters in obstructive kidney disease, we examined the mRNA expression of sodium transporters including NHE3, α -Na-K-ATPase, NCC, NKCC2, and three ENaC subunits (α, β, and γ ) via qRT-PCR
The data showed that NHE3, α -Na-K-ATPase, and NCC were markedly downregulated in obstructed kidneys, which was not affected by rotenone administration (Fig. 1A–C)

Summary

Introduction

Obstructive kidney disease is a common clinical complication[1,2,3,4]. In children, kidney obstruction is usually caused by congenital abnormalities of the kidneys and urinary tract[5,6,7]. Results Effects of mitochondrial complex-I inhibition on the mRNA expression of sodium transporters in obstructed kidneys. To study the role of rotenone treatment in the regulation of sodium transporters in obstructive kidney disease, we examined the mRNA expression of sodium transporters including NHE3, α -Na-K-ATPase, NCC, NKCC2, and three ENaC subunits (α , β , and γ ) via qRT-PCR.

Results

Conclusion