Cyclosporin A (CsA) does not only exert a toxic effect on kidney parenchymal cells, but also protects them against necrotic cell death by inhibiting opening of mitochondrial permeability transition ...pore. However, whether CsA plays a role in hydrogen peroxide-induced kidney proximal tubular cell death is currently unclear. In the present study, treatment with CsA further increased apoptosis and necrosis in HK-2 human kidney proximal tubule epithelial cells during exposure to hydrogen peroxide. In addition, hydrogen peroxide-induced p53 activation and BH3 interacting-domain death agonist (BID) expression were higher in CsA-treated cells than those in non-treated cells, whereas hydrogen peroxide-induced activation of mitogen-activated protein kinases including p38, c-Jun N-terminal kinase, and extracellular signal-regulated kinase and activation of protein kinase B were not significantly altered by treatment with CsA. In oxidant-antioxidant system, reactive oxygen species (ROS) production induced by hydrogen peroxide was further enhanced by treatment with CsA. However, expression levels of antioxidant enzymes including manganese superoxide dismutase, copper/zinc superoxide dismutase, and catalase were not altered by treatment with hydrogen peroxide or CsA. Treatment with CsA further enhanced mitochondrial membrane potential induced by exposure to hydrogen peroxide, although it did not alter endoplasmic reticulum stress based on expression of glucose-regulated protein 78 and 94. Taken together, these data suggest that CsA can aggravate hydrogen peroxide-induced cell death through p53 activation, BID expression, and ROS production.
The kidney is innervated by afferent sensory and efferent sympathetic nerve fibers. Norepinephrine (NE) is the primary neurotransmitter for post-ganglionic sympathetic adrenergic nerves, and its ...signaling, regulated through adrenergic receptors (AR), modulates renal function and pathophysiology under disease conditions. Renal sympathetic overactivity and increased NE level are commonly seen in chronic kidney disease (CKD) and are critical factors in the progression of renal disease. Blockade of sympathetic nerve-derived signaling by renal denervation or AR blockade in clinical and experimental studies demonstrates that renal nerves and its downstream signaling contribute to progression of acute kidney injury (AKI) to CKD and fibrogenesis. This review summarizes our current knowledge of the role of renal sympathetic nerve and adrenergic receptors in AKI, AKI to CKD transition and CKDand provides new insights into the therapeutic potential of intervening in its signaling pathways.
Apoptosis, necrosis, and inflammation are hallmarks of cisplatin nephrotoxicity; however, the role and mechanisms of necrosis and inflammation remains undefined. As poly(ADP-ribose) polymerase 1 ...(PARP1) inhibition or its gene deletion is renoprotective in several renal disease models, we tested whether its activation may be involved in cisplatin nephrotoxicity. Parp1 deficiency was found to reduce cisplatin-induced kidney dysfunction, oxidative stress, and tubular necrosis, but not apoptosis. Moreover, neutrophil infiltration, activation of nuclear factor-κB, c-Jun N-terminal kinases, p38 mitogen-activated protein kinase, and upregulation of proinflammatory genes were all abrogated by Parp1 deficiency. Using proximal tubule epithelial cells isolated from Parp1-deficient and wild-type mice and pharmacological inhibitors, we found evidence for a PARP1/Toll-like receptor 4/p38/tumor necrosis factor-α axis following cisplatin injury. Furthermore, pharmacological inhibition of PARP1 protected against cisplatin-induced kidney structural/functional damage and inflammation. Thus, our findings suggest that PARP1 activation is a primary signal and its inhibition/loss protects against cisplatin-induced nephrotoxicity. Targeting PARP1 may offer a potential therapeutic strategy for cisplatin nephrotoxicity.
Inactivation of poly(ADP-ribose) polymerase 1 (PARP1) has been found to be protective in several disease models; however, the role of PARP1 in acute kidney injury-induced interstitial fibrosis has ...not been studied. Herein, we tested whether PARP1 inactivation by treatment with PJ34 (a PARP1 inactivator; 10 mg/kg body weight/day, intraperitoneal implantation of a miniosmotic pump at 2 days after the onset) contributed to the decrease in interstitial fibrosis induced by ischemia-reperfusion injury (IRI) in mouse kidneys. IRI increased PARP1 activation represented by poly(ADP-ribose) expression from 4 to 16 days postinjury, whereas treatment with PJ34 at 2 days after the onset efficaciously abolished the increase in PARP1 activation at 4, 8 and 16 days after IRI. Pharmacological inactivation of PARP1 significantly reduced interstitial fibrosis as represented by the collagen deposition and transforming growth factor-β1 level at 8 and 16 days after IRI. Consistent with collagen deposition, myofibroblast activation represented by α-smooth muscle actin expression was also reduced by PARP1 inactivation at 8 and 16 days after IRI. Furthermore, IRI enhanced macrophage influx, but PARP1 inactivaton remarkably reduced macrophage influx for 4 through 16 days after the injury. Among the chemoattractants for monocytes/macrophages and neutrophils, monocyte chemotactic protein-1 (MCP-1) production in IRI kidneys was significantly reduced by PARP1 inactivation from 4 to 16 days postinjury. These data demonstrate that PARP1 activation contributes to IRI-induced MCP-1 production and in turn to macrophage influx, resulting in the promotion of interstitial fibrosis.
Poly(ADP-ribose) polymerase 1 (PARP1) contributes to necrotic cell death and inflammation in several disease models; however, the role of PARP1 in fibrogenesis remains to be defined. Here, we tested ...whether PARP1 was involved in the pathogenesis of renal fibrosis using the unilateral ureteral obstruction (UUO) mouse model. UUO was performed by ligation of the left ureter near the renal pelvis in Parp1-knockout (KO) and wild-type (WT) male mice. After 10 days of UUO, renal PARP1 expression and activation were strongly increased by 6- and 13-fold, respectively. Interstitial fibrosis induced by UUO was significantly attenuated in Parp1-KO kidneys compared with that in WT kidneys at 10 days, but not at 3 days, based on collagen deposition, α-smooth muscle actin (α-SMA), and fibronectin expression. Intriguingly, the UUO kidneys in Parp1-KO mice showed a dramatic decrease in infiltration of neutrophil and reduction in expression of proinflammatory proteins including intercellular adhesion molecule-1, tumor necrosis factor-α, inducible nitric oxide synthase, and toll-like receptor 4 as well as phosphorylation of nuclear factor-κB p65, but not transforming growth factor-β1 (TGF-β1) at both 3 and 10 days. Pharmacological inhibition of PARP1 in rat renal interstitial fibroblast (NRK-49F) cell line or genetic ablation in primary mouse embryonic fibroblast cells did not affect TGF-β1-induced de novo α-SMA expression. Parp1 deficiency significantly attenuated UUO-induced histological damage in the kidney tubular cells, but not apoptosis. These data suggest that PARP1 induces necrotic cell death and contributes to inflammatory signaling pathways that trigger fibrogenesis in obstructive nephropathy.
Aristolochic acid (AA) is notorious for inducing nephrotoxicity, but the influence of sex on AA-induced kidney injury was not clear. This study sought to investigate sex differences in kidney ...dysfunction and tubular injury induced by AA. Male and female mice were bilaterally orchiectomized and ovariectomized, respectively. Fourteen days after gonadectomy, the mice were intraperitoneally injected with AA (10 mg/kg body weight/day) daily for 2 days and sacrificed 7 days after the first injection. Body weight, kidney function, and tubular structure were assessed. When compared between male and female non-gonadectomized mice, AA-induced body weight loss was greater in male mice than in female mice. Functional and structural damages in male kidneys were markedly induced by AA injection, but kidneys in AA-injected female mice showed no or mild damages. Ovariectomy had no effect on AA-induced nephrotoxic acute kidney injury in female mice. However, orchiectomy significantly reduced body weight loss, kidney dysfunction, and tubular injury in AA-induced nephrotoxicity in male mice. This study has demonstrated that testis causes AA-induced nephrotoxic acute kidney injury.
Ischemic preconditioning by a single event of ischemia and reperfusion (SIRPC) dramatically protects renal function against ischemia and reperfusion (I/R) induced several weeks later. We recently ...reported that reactive oxygen species (ROS) and oxidative stress were sustained in a kidney that had functionally recovered from I/R injury, thus suggesting an association between SIRPC and ROS and oxidative stress. However, the role of ROS in SIRPC remains to be clearly elucidated. To assess the involvement of ROS in SIRPC, mice were subjected to SIRPC (30 min of bilateral renal ischemia and 8 days of reperfusion) and then exposed to I/R injury. Thirty minutes of bilateral renal ischemia in the non-SIRPC mice resulted in a marked increase in plasma creatinine levels 4 and 24 h after reperfusion, which was not observed in the I/R in the SIRPC mice. SIRPC resulted in increases in the levels of kidney superoxide. Administrations of manganese(III) tetrakis(1-methyl-4-pyridyl) porphyrin MnTMPyP; a cell-permeable superoxide dismutase (SOD) mimetic and N-acetylcysteine (NAc; a ROS scavenger) to SIRPC mice blocked the SIRPC-induced increase in superoxide levels and removed approximately 48-64% of the functional protection of the SIRPC kidney. Additionally, these administrations significantly inhibited I/R-induced increases in superoxide formation, hydrogen peroxide production, and lipid peroxidation, along with the inhibition of I/R-induced reductions in the expression and activity of manganese SOD, copper-zinc SOD, and catalase. Furthermore, administrations of MnTMPyP or NAc inhibited the SIRPC-induced increase in inducible nitric oxide synthase expression but did not inhibit the SIRPC-induced increases in heat shock protein-25 expression. In conclusion, the renoprotection afforded by SIRPC was triggered by ROS generated by SIRPC.
OBJECTIVE The purpose of this study was to investigate the incidence of seizures during the intraoperative monitoring of motor evoked potentials (MEPs) elicited by electrical brain stimulation in a ...wide spectrum of surgeries such as those of the orthopedic spine, spinal cord, and peripheral nerves, interventional radiology procedures, and craniotomies for supra- and infratentorial tumors and vascular lesions. METHODS The authors retrospectively analyzed data from 4179 consecutive patients who underwent surgery or an interventional radiology procedure with MEP monitoring. RESULTS Of 4179 patients, only 32 (0.8%) had 1 or more intraoperative seizures. The incidence of seizures in cranial procedures, including craniotomies and interventional neuroradiology, was 1.8%. In craniotomies in which transcranial electrical stimulation (TES) was applied to elicit MEPs, the incidence of seizures was 0.7% (6/850). When direct cortical stimulation was additionally applied, the incidence of seizures increased to 5.4% (23/422). Patients undergoing craniotomies for the excision of extraaxial brain tumors, particularly meningiomas (15 patients), exhibited the highest risk of developing an intraoperative seizure (16 patients). The incidence of seizures in orthopedic spine surgeries was 0.2% (3/1664). None of the patients who underwent surgery for conditions of the spinal cord, neck, or peripheral nerves or who underwent cranial or noncranial interventional radiology procedures had intraoperative seizures elicited by TES during MEP monitoring. CONCLUSIONS In this largest such study to date, the authors report the incidence of intraoperative seizures in patients who underwent MEP monitoring during a wide spectrum of surgeries such as those of the orthopedic spine, spinal cord, and peripheral nerves, interventional radiology procedures, and craniotomies for supra- and infratentorial tumors and vascular lesions. The low incidence of seizures induced by electrical brain stimulation, particularly short-train TES, demonstrates that MEP monitoring is a safe technique that should not be avoided due to the risk of inducing seizures.
Kidney denervation prevents the development of tubulointerstitial fibrosis, but local infusion of calcitonin gene‐related peptide (CGRP) into the denervated kidneys upregulates profibrogenic growth ...factors and restores the fibrotic feature. However, it is not clear how CGRP contributes to the upregulation of profibrogenic factors.
Both human HK‐2 and pig LLC‐PK1 kidney proximal tubular cells undergoing a 6 hours exposure to CGRP were treated with CGRP receptor antagonist (CGRP8–37), a specific protein kinase C (PKC) inhibitor chelerythrine, or a potent JNK inhibitor SP600125. Levels of transforming growth factor‐β1 (TGF‐β1) production and PKC activity were measured by enzyme‐linked immunosorbent assay. Western blot analysis performed to determine the protein levels of connective tissue growth factor (CTGF) expression and c‐Jun N‐terminal protein kinase (JNK) phosphorylation.
Administration of 1 nM CGRP significantly increased the levels of TGF‐β1 production and CTGF expression at 6 and 24 hours after the onset. The exogenous CGRP also increased their protein levels in the incubation media, indicating release of their proteins from the cells. Treatment with 100 nM CGRP8–37 immediately after the onset significantly inhibited the increase in intracellular and released protein levels of TGF‐β1 and CTGF during CGRP exposure. Furthermore, treatment with 1 thru 10 μM chelerythrine markedly reduced the upregulation and release of TGF‐β1 and CTGF after 6 hours exposure to CGRP. Finally, inhibition of JNK phosphorylation using 1 μM SP600125 prevented the increase in TGF‐β1 and CTGF upregulation and release after 6 hours exposure to CGRP.
Exogenous CGRP induces the upregulation and secretion of profibrogenic TGF‐β1 and CTGF proteins through CGRP receptor/PKC/JNK signaling pathway in proximal tubular cells, and this pathway might be a cause of triggering inflammation cascade and tubulointerstitial fibrosis.
Support or Funding Information
This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT & Future Planning (NRF‐2016R1C1B2012080).
This is from the Experimental Biology 2019 Meeting. There is no full text article associated with this published in The FASEB Journal.
To analyze malignancy of computed tomography (CT) and magnetic resonance imaging (MRI) results in the same renal mass.
We retrospectively reviewed 1,216 patients who underwent partial nephrectomy ...from January 2017 to December 2021 in our institute. Patients who had both CT and MRI reports prior to surgery were included. We compared the diagnostic accuracy between the CT and the MRI. The patients were divided into two groups according to the consistency of reports: the 'Consistent group' and the 'Inconsistent group'. The Inconsistent group was further divided into two subgroups. Group 1 is the case that showed benign findings on CT but malignancy on MRI. Group 2 is the cases of malignancy on CT but benign on MRI.
410 patients were identified. Benign lesion was identified in 68 cases (16.6%). The sensitivity, specificity and diagnostic accuracy of MRI was 91.2%, 36.8%, and 82.2% respectively, whereas that of CT was 84.8%, 41.2%, and 77.6% respectively. Consistent group were 335 cases (81.7%) and inconsistent group were 75 cases (18.3%). The mean mass size was significantly smaller in the inconsistent group compared to the consistent group (consistent group vs. inconsistent group: 2.31±0.84 cm vs.1.84±0.75 cm, p<0.001). Also, the Group 1 had higher odds of malignancy compared to Group 2 in the renal mass size 2-4 cm (odds ratio, 5.62 1.02-30.90).
Smaller mass size affects the discrepancy of CT and MRI reports. In addition, MRI showed better diagnostic performance in mismatch cases in the small renal masses.
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