Leptin Induces Oxidative Stress Through Activation of NADPH Oxidase in Renal Tubular Cells: Antioxidant Effect of L-Carnitine

Obesity is a risk factor for chronic kidney disease (CKD) progression. Circulating levels of adiponectin, an adipokine, decrease with obesity and play a protective role in the cardiovascular system. We hypothesized that adiponectin might also protect the kidney. Because activation of the renin-angiotensin system (RAS) is a contributor to CKD progression, we tested our hypothesis by studying the interactions between adiponectin and angiotensin II (ANG II) in renal tubular cells. Primary human renal proximal tubule cells expressed both adiponectin receptor 1 and 2 (adipoR1 and R2). ANG II-induced NADPH oxidase activation and oxidative stress were attenuated by adiponectin and dependent on adipoR1. Activation of AMPK with 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside (AICAR) mimicked, while inhibition of AMPK with compound C abrogated, the effect of adiponectin on ANG II-induced activation of NADPH oxidase. Similarly, the effect of adiponectin was recapitulated by the stable cAMP analogs 4-chlorophenylthio (pCPT)-cAMP and dibutyryl (db)-cAMP and blocked by the adenylate cyclase inhibitor SQ22536. Adiponectin did not activate PKA in renal tubular cells, and the specific PKA inhibitor myristoylated PKI (14–22) amide failed to block the inhibitory effect of adiponectin on ANG II-induced NADPH oxidase activation. In contrast, the specific Epac activator 8-(4-chlorophenylthio)-2′-O-methyl (8-CPT-2-O-Me)-cAMP blocked ANG II-induced activation of NADPH oxidase, an effect that was reversed by coincubation with the AMPK inhibitor compound C. Finally, adiponectin attenuated ANG II-induced NF-κB activation and fibronectin protein expression. These in vitro findings support the hypothesis that adiponectin may attenuate the deleterious effects of ANG II in the kidney and play a protective role in CKD.

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Nitro-oleic acid ameliorates oxygen and glucose deprivation/re-oxygenation triggered oxidative stress in renal tubular cells via activation of Nrf2 and suppression of NADPH oxidase

Free Radical Research ◽

10.1080/10715762.2016.1225955 ◽

2016 ◽

Vol 50 (11) ◽

pp. 1200-1213 ◽

Cited By ~ 13

Author(s):

Huibin Nie ◽

Xia Xue ◽

Gang Liu ◽

Guangju Guan ◽

Haiying Liu ◽

...

Keyword(s):

Oxidative Stress ◽

Oleic Acid ◽

Nadph Oxidase ◽

Glucose Deprivation ◽

Oxygen And Glucose Deprivation ◽

Tubular Cells ◽

Renal Tubular Cells ◽

Renal Tubular

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Losartan Ameliorates Calcium Oxalate-Induced Elevation of Stone-Related Proteins in Renal Tubular Cells by Inhibiting NADPH Oxidase and Oxidative Stress

Oxidative Medicine and Cellular Longevity ◽

10.1155/2018/1271864 ◽

2018 ◽

Vol 2018 ◽

pp. 1-12 ◽

Cited By ~ 11

Author(s):

Baolong Qin ◽

Qing Wang ◽

Yuchao Lu ◽

Cong Li ◽

Henglong Hu ◽

...

Keyword(s):

Oxidative Stress ◽

Nadph Oxidase ◽

Calcium Oxalate ◽

Stone Formation ◽

Ang Ii ◽

Tubular Cells ◽

Renal Tubular Cells ◽

Renal Tubular ◽

Related Proteins ◽

And Oxidative Stress

Calcium oxalate (CaOx) is the most common type of urinary stone. Increase of ROS and NADPH oxidase gives rise to inflammation and injury of renal tubular cells, which promotes CaOx stone formation. Recent studies have revealed that the renin-angiotensin system might play a role in kidney crystallization and ROS production. Here, we investigated the involvement of Ang II/AT1R and losartan in CaOx stone formation. NRK-52E cells were incubated with CaOx crystals, and glyoxylic acid-induced hyperoxaluric rats were treated with losartan. Oxidative stress statuses were evaluated by detection of ROS, oxidative products (8-OHdG and MDA), and antioxidant enzymes (SOD and CAT). Expression of NADPH oxidase subunits (Nox2 and Nox4), NF-κB pathway subunits (p50 and p65), and stone-related proteins such as OPN, CD44, and MCP-1 was determined by Western blotting. The results revealed upregulation of Ang II/AT1R by CaOx treatment. CaOx-induced ROS and stone-related protein upregulation were mediated by the Ang II/AT1R signaling pathway. Losartan ameliorated renal tubular cell expression of stone-related proteins and renal crystallization by inhibiting NADPH oxidase and oxidative stress. We conclude that losartan might be a promising preventive and therapeutic candidate for hyperoxaluria nephrolithiasis.

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Telmisartan Attenuates Uric Acid-Induced Epithelial-Mesenchymal Transition in Renal Tubular Cells

BioMed Research International ◽

10.1155/2019/3851718 ◽

2019 ◽

Vol 2019 ◽

pp. 1-12 ◽

Cited By ~ 5

Author(s):

Dongqing Zha ◽

Saiqun Wu ◽

Ping Gao ◽

Xiaoyan Wu

Keyword(s):

Uric Acid ◽

Epithelial Cells ◽

Nadph Oxidase ◽

Dependent Manner ◽

Tubular Epithelial Cells ◽

Mesenchymal Transition ◽

Tubular Cells ◽

Renal Tubular Cells ◽

Diphenylene Iodonium ◽

Renal Tubular

We examined whether and how uric acid induces epithelial to mesenchymal transition (EMT) in renal tubular cells, along with the mechanism by which telmisartan acts on uric acid-induced renal injury. Rat renal proximal tubular epithelial cells (NRK-52E) were exposed to various concentrations of uric acid in the presence or absence of telmisartan. Treatment with uric acid increased the expression of α-SMA, decreased the expression of E-cadherin, and promoted EMT in NRK-52E cells. Uric acid treatment also led to increased endothelin-1 (ET-1) production, activation of extracellular-regulated protein kinase 1/2 (ERK1/2), and the upregulation of nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4). Use of ET-1 receptor inhibitor (BQ123 or BQ788) could inhibit uric acid-induced EMT in NRK-52E cells. Pretreatment with the ERK inhibitor (U0126 or PD98059) suppressed the release of ET-1 and EMT induced by uric acid. Additionally, pretreatment with a traditional antioxidant (diphenylene iodonium or apocynin) inhibited the activation of ERK1/2, release of ET-1, and uric acid-induced EMT in NRK-52E cells. These findings suggested that uric acid-induced EMT in renal tubular epithelial cells occurs through NADPH oxidase-mediated ERK1/2 activation and the subsequent release of ET-1. Furthermore, telmisartan (102 nmol/L to 104 nmol/L) inhibited the expression of NOX4, intracellular reactive oxygen species (ROS), activation of ERK1/2, and the release of ET-1 in a dose-dependent manner, thereby preventing uric acid-induced EMT in NRK-52E. In conclusion, telmisartan could ameliorate uric acid-induced EMT in NRK-52E cells likely through inhibition of the NADPH oxidase/ERK1/2/ET-1 pathway.

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