Abstract
Ureteral obstruction is associated with reduced expressions of renal sodium transporters, which contributes to impaired urinary concentrating capacity. In this study, we employed a synthetic mitochondrial superoxide dismutase 2 (SOD2) mimic MnTBAP to investigate the role of mitochondrial oxidative stress in modulating the sodium transporters in obstructive kidney disease. Following unilateral ureteral obstruction (UUO) for 7 days, a global reduction of sodium transporters including NHE3, NCC, NKCC2, and ENaCα was observed as determined by qRT-PCR, Western Blotting or immunohistochemistry. Among these sodium transporters, the downregulation of NHE3, NCC, and NKCC2 was partially reversed by MnTBAP treatment. In contrast, the reduction of ENaCα was not affected by MnTBAP. The β and γ subunits of ENaC were not significantly altered by ureteral obstruction or MnTBAP therapy. To further confirm the anti-oxidant effect of MnTBAP, we examined the levels of TBARs in the urine collected from the obstructed ureters of UUO mice and bladder of sham mice. As expected, the increment of urinary TBARs in UUO mice was entirely abolished by MnTBAP therapy, indicating an amelioration of oxidative stress. Meantime, we found that three types of SOD were all reduced in obstructed kidneys determined by qRT-PCR, which was unaffected by MnTBAP. Collectively, these results demonstrated an important role of mitochondrial oxidative stress in mediating the downregulation of sodium transporters in obstructive kidney disease.
Highlights
Unilateral ureteral obstruction (UUO) is a wellestablished experimental rodent model that mimics the complex pathophysiology of chronic obstructive nephropathy in an accelerated manner
It has been well documented that the abundance of sodium transporters was significantly reduced in response to ureteral obstruction, which at least partially contribute to the impaired urine concentrating capacity after the release of urinary tract obstruction [1, 13,14,15]
Consistent with previous finding, our data showed that the renal expression of sodium transporters including NHE3, NCC, NKCC2, and ENaCα were robustly decreased after ureteral obstruction while the expression of ENaCγ was not significantly changed in obstructed kidneys
Summary
Unilateral ureteral obstruction (UUO) is a wellestablished experimental rodent model that mimics the complex pathophysiology of chronic obstructive nephropathy in an accelerated manner. It has been demonstrated that both Angiotensin (Ang) II [2] and cyclooxygenase-2 (COX-2)derived prostaglandin E2 (PGE2) [3] mediated the decrease of sodium transporters in obstructive kidneys. Liu et al demonstrated that NOX-derived ROS are partially responsible for the downregulation of renal tubular Na/K-ATPase expression in acute UUO rats [10]. Our group reported that inhibition of mitochondrial complex-1 reversed the downregulation of aquaporins [11] and sodium transporters including NKCC2 and ENaCα [12] in obstructive nephropathy. Whether mitochondria-derived ROS is involved in the downregulation of sodium transporters during kidney obstruction is not known. In the present study, we employed manganese (III) tetrakis (4-benzoic acid) porphyrin chloride (MnTBAP), a synthetic mitochondrial superoxide dismutase 2 (SOD2) mimic, to investigate whether mitochondrial ROS could affect the downregulation of sodium transporters in the obstructed kidneys
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