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

Zhang Y, Sun Y, Ding G, Huang S, Zhang A, Jia Z - Sci Rep (2015)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: 1] Department of Nephrology, Nanjing Children's Hospital, Affiliated with Nanjing Medical University, Nanjing 210008, China [2] Institute of Pediatrics, Nanjing Medical University, Nanjing, China [3] Nanjing Key Laboratory of Pediatrics, Nanjing Children Hospital, Affiliated with Nanjing Medical University, Nanjing 210008, China.

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.

No MeSH data available.


Related in: MedlinePlus

mRNA expression of sodium transporters in obstructed kidneys following rotenone treatment.(A) qRT-PCR analysis of NHE3. (B) qRT-PCR analysis of NCC. (C) qRT-PCR analysis of α-Na-K-ATPase. (D) qRT-PCR analysis of NKCC2. (E) qRT-PCR analysis of ENaCα. (F) qRT-PCR analysis of ENaCβ. (G) qRT-PCR analysis of ENaCγ. The presented data are means ± SE. N = 5 in each group.
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f1: mRNA expression of sodium transporters in obstructed kidneys following rotenone treatment.(A) qRT-PCR analysis of NHE3. (B) qRT-PCR analysis of NCC. (C) qRT-PCR analysis of α-Na-K-ATPase. (D) qRT-PCR analysis of NKCC2. (E) qRT-PCR analysis of ENaCα. (F) qRT-PCR analysis of ENaCβ. (G) qRT-PCR analysis of ENaCγ. The presented data are means ± SE. N = 5 in each group.

Mentions: 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). In contrast, a marked reduction of NKCC2 mRNA expression was partially, but significantly reversed by rotenone treatment (Fig. 1D). For the three ENaC subunits, the downregulation of ENaCα in obstructed kidneys was completely inhibited by rotenone (Fig. 1E). However, the mRNA levels of ENaCβ and ENaCγ were not altered by ureteral obstruction or rotenone treatment (Fig. 1F,G).


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

Zhang Y, Sun Y, Ding G, Huang S, Zhang A, Jia Z - Sci Rep (2015)

mRNA expression of sodium transporters in obstructed kidneys following rotenone treatment.(A) qRT-PCR analysis of NHE3. (B) qRT-PCR analysis of NCC. (C) qRT-PCR analysis of α-Na-K-ATPase. (D) qRT-PCR analysis of NKCC2. (E) qRT-PCR analysis of ENaCα. (F) qRT-PCR analysis of ENaCβ. (G) qRT-PCR analysis of ENaCγ. The presented data are means ± SE. N = 5 in each group.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4513566&req=5

f1: mRNA expression of sodium transporters in obstructed kidneys following rotenone treatment.(A) qRT-PCR analysis of NHE3. (B) qRT-PCR analysis of NCC. (C) qRT-PCR analysis of α-Na-K-ATPase. (D) qRT-PCR analysis of NKCC2. (E) qRT-PCR analysis of ENaCα. (F) qRT-PCR analysis of ENaCβ. (G) qRT-PCR analysis of ENaCγ. The presented data are means ± SE. N = 5 in each group.
Mentions: 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). In contrast, a marked reduction of NKCC2 mRNA expression was partially, but significantly reversed by rotenone treatment (Fig. 1D). For the three ENaC subunits, the downregulation of ENaCα in obstructed kidneys was completely inhibited by rotenone (Fig. 1E). However, the mRNA levels of ENaCβ and ENaCγ were not altered by ureteral obstruction or rotenone treatment (Fig. 1F,G).

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: 1] Department of Nephrology, Nanjing Children's Hospital, Affiliated with Nanjing Medical University, Nanjing 210008, China [2] Institute of Pediatrics, Nanjing Medical University, Nanjing, China [3] Nanjing Key Laboratory of Pediatrics, Nanjing Children Hospital, Affiliated with Nanjing Medical University, Nanjing 210008, China.

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.

No MeSH data available.


Related in: MedlinePlus