Inhibition of Nuclear Factor-κB Activation Attenuates Tubulointerstitial Nephritis Induced by Gentamicin

Volpini, Rildo Aparecido; Costa, R. S.; Silva, Cleonice G. A. da; Coimbra, Terezila Machado

doi:10.1159/000081558

Cited by 35 publications

(47 citation statements)

References 37 publications

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“…In the GM rat model, NF-κB was activated by GM administration, and blockade of NF-κB activation reduced apoptosis and interstitial fibrosis. 23 NF-κB is released from an inhibitory subunit I-κB and translocates into the nucleus, where it promotes the transcriptional activation of target genes. 6 In our study, the expression of nuclear p65 subunits of NF-κB increased after GM treatment in HK-2 cells, which suggests that GM induced NF-κB activation and translocation via I-κB degradation.…”

Section: Discussionmentioning

confidence: 99%

Renoprotective effects of the direct renin inhibitor aliskiren on gentamicin-induced nephrotoxicity in rats

Bae

Kim

Joo

et al. 2013

J Renin Angiotensin Aldosterone Syst

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This study aimed to examine the protective effects of aliskiren on gentamicin-induced nephropathy. Rats were injected with gentamicin (100 mg/kg per day) for 14 days. Aliskiren was infused for two weeks. Human proximal tubular epithelial cell lines (HK-2) were cultured with gentamicin in the absence or presence of aliskiren. Inflammatory profibrotic and apoptotic markers were evaluated in vivo and in vitro. Aliskiren treatment attenuated the decreased creatinine clearance, increased fractional sodium excretion, glomerulosclerosis and tubulointerstitial fibrosis and counteracted the increased ED-1 expression in gentamicin-treated rats. The levels of inflammatory cytokines (TNF-α, IL-1β and IFN-γ) and adhesion molecules (MCP-1, ICAM-1 and VCAM-1) increased in the gentamicin-treated kidneys. These changes were restored by aliskiren co-treatment. Aliskiren effectively reversed transforming growth factor-β-induced fibrotic responses such as induction of α-smooth muscle actin in gentamicin-treated rat kidneys. Along with these changes, aliskiren also attenuated the increase in nuclear factor κB and phosphorylated extracellular signal-regulated kinase (pERK 1/2) levels in HK-2 cells cultured with gentamicin. In addition, aliskiren decreased the number of TUNEL-positive nuclei and reduced the expression of proapoptotic markers in gentamicin-treated HK-2 cells. These findings suggest that aliskiren attenuates gentamicin-induced nephropathy by suppression of inflammatory, profibrotic and apoptotic factors through inhibition of the nuclear factor κB, Smads and mitogen-activated protein kinase signaling pathways.

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Section: Discussionmentioning

confidence: 99%

Renoprotective effects of the direct renin inhibitor aliskiren on gentamicin-induced nephrotoxicity in rats

Bae

Kim

Joo

et al. 2013

J Renin Angiotensin Aldosterone Syst

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“…In unilateral ureteral obstruction (UUO) and the GM rat model, NF-B was activated, followed by UUO or GM administration, and blockade of NF-B activation reduced apoptosis and interstitial fibrosis (23,39). NF-B is released from an inhibitory subunit IB and translocates into the nucleus, where it promotes the transcriptional activation of target genes (10).…”

Section: Discussionmentioning

confidence: 99%

Renoprotective effects of paricalcitol on gentamicin-induced kidney injury in rats

Park¹,

Bae²,

Kim³

et al. 2010

American Journal of Physiology-Renal Physiology

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Vitamin D is thought to exert a protective effect on renal disease progression, but the underlying molecular mechanism remains unclear. We investigated whether paricalcitol ameliorates tubular dysfunction and fibrosis in gentamicin (GM)-induced renal injury. Two groups of rats were treated with GM (100 mg·kg−1·day−1), one of which was cotreated with paricalcitol (0.3 μg·kg−1·day−1) for 14 days and the other was not. The control group was treated with vehicle only. HK-2 cells were cultured with GM in the absence or presence of paricalcitol. Paricalcitol restored impaired renal function and the downregulated renal sodium transporters and aquaporin-1 expression caused by GM. ED-1-expressing monocyte/macrophage accumulation induced by GM was attenuated by paricalcitol treatment. Paricalcitol prevented upregulated inflammatory cytokines (TNF-α, IL-1β, INF-γ) and adhesion molecules (monocyte chemoattractant protein-1, ICAM-1, VCAM-1) induced by GM. In addition, paricalcitol effectively reversed TGF-β1-induced epithelial-to-mesenchymal transition (EMT) process and extracellular matrix accumulation in GM-induced nephropathy. Increased collagen deposition and fibrosis in GM-treated kidney were ameliorated by paricalcitol. Paricalcitol also attenuated the upregulated NF-κB and phosphorylated ERK1/2 expression in HK-2 cells cultured with GM. In conclusion, paricalcitol prevents GM-induced renal injury by inhibiting renal inflammation and fibrosis, the mechanism of which is the interruption of NF-κB/ERK signaling pathway and preservation of tubular epithelial integrity via inhibiting EMT process.

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“…In each renal cortex, 20 grid fields (each measuring 37,000 m 2 ) were evaluated. Interstitial areas were first manually encircled on a video screen and then quantified by computerized morphometry (47).…”

Section: Methodsmentioning

confidence: 99%

Erythropoietin prevents sepsis-related acute kidney injury in rats by inhibiting NF-κB and upregulating endothelial nitric oxide synthase

Souza

Volpini

Shimizu

et al. 2012

American Journal of Physiology-Renal Physiology

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de Souza ACCP, Volpini RA, Shimizu MH, Sanches TR, Camara NOS, Semedo P, Rodrigues CE, Seguro AC, Andrade L. Erythropoietin prevents sepsis-related acute kidney injury in rats by inhibiting nuclear factor-B and upregulating endothelial nitric oxide synthase. Am J Physiol Renal Physiol 302: F1045-F1054, 2012. First published January 11, 2012 doi:10.1152/ajprenal.00148.2011.-The pathophysiology of sepsis involves complex cytokine and inflammatory mediator networks, a mechanism to which NF-B activation is central. Downregulation of endothelial nitric oxide synthase (eNOS) contributes to sepsis-induced endothelial dysfunction. Erythropoietin (EPO) has emerged as a major tissue-protective cytokine in the setting of stress. We investigated the role of EPO in sepsis-related acute kidney injury using a cecal ligation and puncture (CLP) model. Wistar rats were divided into three primary groups: control (sham-operated); CLP; and CLPϩEPO. EPO (4,000 IU/kg body wt ip) was administered 24 and 1 h before CLP. Another group of rats received N-nitro-L-arginine methyl ester (L-NAME) simultaneously with EPO administration (CLPϩEPOϩL-NAME). A fifth group (CLPϩEPOtreat) received EPO at 1 and 4 h after CLP. At 48 h postprocedure, CLPϩEPO rats presented significantly higher inulin clearance than did CLP and CLPϩEPOϩL-NAME rats; hematocrit levels, mean arterial pressure, and metabolic balance remained unchanged in the CLPϩEPO rats; and inulin clearance was significantly higher in CLPϩEPOtreat rats than in CLP rats. At 48 h after CLP, creatinine clearance was significantly higher in the CLPϩEPO rats than in the CLP rats. In renal tissue, pre-CLP EPO administration prevented the sepsis-induced increase in macrophage infiltration, as well as preserving eNOS expression, EPO receptor (EpoR) expression, IKK-␣ activation, NF-B activation, and inflammatory cytokine levels, thereby increasing survival. We conclude that this protection, which appears to be dependent on EpoR activation and on eNOS expression, is attributable, in part, to inhibition of the inflammatory response via NF-B downregulation.THE MORTALITY RATES OF SEPSIS and septic shock remain unacceptably high and have not changed in several decades (5,6,26,30). Acute kidney injury (AKI) occurs in ϳ50% of patients with sepsis (5, 30). In such patients, the development of AKI is predictive of a poor outcome, and the consequent mortality has been reported to be as high as 70% (5). Despite improved strategies for supporting vital organs and resuscitating patients, the incidence and mortality rates of septic AKI remain quite high (5, 6). The prevention of kidney injury in intensive care settings continues to represent a great challenge.It has been shown that NF-B mediates the transcription of a large number of genes, the products of which are known to play important roles in septic pathophysiology (24, 31). Mice deficient in those NF-B-dependent genes are resistant to the development of septic shock and to sepsis-related mortality (31). More importantly, blockade of the NF-B pathway corr...

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Inhibition of Nuclear Factor-κB Activation Attenuates Tubulointerstitial Nephritis Induced by Gentamicin

Cited by 35 publications

References 37 publications

Renoprotective effects of the direct renin inhibitor aliskiren on gentamicin-induced nephrotoxicity in rats

Renoprotective effects of the direct renin inhibitor aliskiren on gentamicin-induced nephrotoxicity in rats

Renoprotective effects of paricalcitol on gentamicin-induced kidney injury in rats

Erythropoietin prevents sepsis-related acute kidney injury in rats by inhibiting NF-κB and upregulating endothelial nitric oxide synthase

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