MnTBAP therapy attenuates the downregulation of sodium transporters in obstructive kidney disease

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.

Dapagliflozin ameliorates pancreatic injury and activates kidney autophagy by modulating the AMPK/mTOR signaling pathway in obese rats

“…The tissues were homogenized and centrifuged at 1600 g for 10 min at 4°C. Supernatants were collected and malondialdehyde (MDA) concentration in pancreatic tissues was measured using a thiobarbituric acid reactive substances assay kit (Cayman Chemical Company) according to the manufacturer's protocol (Liu et al, 2018). The protein concentration was measured using the Bradford protein assay kit (Bio‐Rad Laboratories).…”

Manganese Superoxide Dismutase Dysfunction and the Pathogenesis of Kidney Disease

“…Oxidative stress and inflammation are closely associated with the pathogenesis of UUO-induced renal fibrosis ( Chevalier et al, 2009 ). In the kidney of UUO mice, the expression of antioxidative enzymes, including Mn-SOD, is reduced, resulting in mitochondrial oxidative stress, inflammation, and tubular epithelial–mesenchymal transition (EMT; Li et al, 2017 ; Liu et al, 2017 ). This condition can be improved by treatment with MnTBAP ( Li et al, 2017 ; Liu et al, 2017 ).…”

“…Administration of MnTMPyP resulted in diminished lipid peroxidation and reduced nitrotyrosine content in the proximal tubular area in association with reductions in caspase-3 activation and tubular epithelial cell damage after I/R injury in rats ( Liang et al, 2009 ). Similarly, administration of Mn (III) meso-tetrakis (N-n-hexylpyridinium-2-yl) porphyrin (MnTnHex-2-PyP 5+ ) or Mn (III) tetrakis (4-benzoic acid) porphyrin chloride (MnTBAP) also resulted in protection against the deleterious effects associated with I/R-induced AKI ( Dorai et al, 2011 ) as well as in the albumin-overload kidney injury ( Zhuang et al, 2015 ; Jia et al, 2016 ) and the UUO model ( Liu et al, 2017 ). Moreover, mitochondria-targeted carboxy-proxyl (Mito-CP) is a five-membered nitroxide CP conjugated to the TTP cation.…”