Targeting immune cell glutamyl-prolyl-transfer RNA synthetase 1 (EPRS1) to prevent fibrosis after tubulointerstitial nephritis.

Glutamyl-prolyl-transfer RNA synthetase 1 is an enzyme that connects glutamic acid and proline to transfer RNA during protein synthesis. In this issue, a study by Kang et al. examined the role of the immune cell glutamyl-prolyl-transfer RNA synthetase 1 in toxin-induced tubulointerstitial nephritis mice. The study demonstrated that blocking glutamyl-prolyl-transfer RNA synthetase 1 may be a therapeutic target to attenuate fibrosis after toxin-induced tubulointerstitial nephritis.

NCTD Prevents Renal Interstitial Fibrosis via Targeting Sp1/lncRNA Gm26669 Axis.

In our previous study, we demonstrated that norcantharidin (NCTD) is a potential therapeutic agent for renal interstitial fibrosis (RIF). Recently, we found that lncRNA Gm26669 (Gm26669) contributed to the development of RIF and could be regulated by NCTD. However, the upstream mechanisms of Gm26669 and whether the anti-RIF effects of NCTD are related to its regulatory action on Gm26669 remain unclear. Our bioinformatics analysis indicated that special protein1 (Sp1), a transcription factor, may bind to the promoter of Gm26669. In the present study, we observed a significant increase in the nuclear translocation of Sp1 using both in vivo and in vitro models of RIF. Furthermore, the knockdown of Sp1 inhibited the expression of collagen type I (CoL-I) and fibronectin (Fn). Mechanistically, Sp1 promoted the expression levels of CoL-I and Fn by directly binding to the promoter of Gm26669 to elevate its expression level. Moreover, we found that NCTD alleviated RIF by inhibiting Gm26669 and the nuclear translocation of Sp1. Collectively, above results suggested that NCTD might prevent RIF via targeting the Sp1/Gm26669 axis, thus providing a new theoretical basis for the clinical application of NCTD in the treatment of RIF.

Chrysophanol ameliorates renal interstitial fibrosis by inhibiting the TGF-ß/Smad signaling pathway.

Renal interstitial fibrosis (RIF) is a major pathological feature of chronic kidney disease at middle and end stages. Chrysophanol (CP), 1,8-dihydroxy-3-methyl-9,10-anthraquinone, is an anthraquinone isolated from Rheum palmatum L. with a variety of pharmacological activities including the suppression of RIF. However, the effect of CP on renal fibrosis and its potential mechanism have not been elucidated. We conducted a comprehensive study by determining the expression levels of fibrotic markers and proteins including TGF-ß1, α-SMA, and Smad3 related to transforming growth factor-beta/Smad (TGF-ß/Smad) pathway in unilateral ureteral obstruction (UUO) mice and TGF-ß1-stimulated HK-2 cells with the treatment of CP using western blotting and RT-qPCR analyses. Using small interfering RNA and co-immunoprecipitation, we evaluated the influences of CP on the interactions between Smad3 and Smad7 proteins and also on TGF-ß RI and TGF-ßR II. We found that CP administration significantly ameliorated UUO-induced kidney damage by reversing abnormal serum and urine biochemical parameters and decreasing the production of fibrotic markers including collagen I, collagen III, fibronectin, and α-SMA. Our results showed that TGF-ß1 and phospho-Smad3 (p-Smad3) expression was significantly down-regulated and Smad7 expression was up-regulated by CP in UUO mice compared to the model group; however, the expression of Smad2, Smad4, and TGF-ß receptors was not affected. Furthermore, CP modulated these fibrotic markers as well as p-Smad3 and Smad7 in TGF-ß1-induced HK-2 cells. The inhibitory effect of CP was markedly reduced in TGF-ß1-treated HK-2 cells transfected with Smad3 siRNA. Additionally, co-immunoprecipitation analysis indicated that CP blocked the interaction between Smad3 and TGF-ß receptor I to suppress p-Smad3 expression. These findings demonstrated that CP alleviated RIF by inhibiting Smad3 phosphorylation, which provides a molecular basis for a new drug candidate for the treatment of RIF.

Munc18-1-interacting protein 3 mitigates renal fibrosis through protection of tubular epithelial cells from apoptosis.

BACKGROUND: Tubulointerstitial fibrosis is a hallmark of chronic kidney disease (CKD), and is initiated by tubular epithelial cell (TEC) injury. Hypoxia promotes tubular cell death, fibrosis and CKD progression. Munc18-1-interacting protein 3 (Mint3) is a molecule that activates hypoxia-inducible factors (HIFs) by binding and suppressing factor inhibiting HIF-1 (FIH). However, the role of Mint3 in tubulointerstitial fibrosis remains unknown. METHODS: We induced fibrosis of the kidney after unilateral ischemia-reperfusion injury (uIRI) in Mint3-knockout and littermate wild-type mice. The duration of ischemia was 23 min and the kidneys were harvested at 24 h and 7 days after ischemia-reperfusion. The function of Mint3 was further investigated by using mouse cortical tubular (MCT) cells, which were treated with Mint3 and/or FIH small interfering RNA and exposed to normoxia or hypoxia. RESULTS: Knockout of Mint3 did not affect the acute injury induced by uIRI, but exacerbated the tubulointerstitial fibrosis, accompanied by an increase in TEC apoptosis. Consistently, hypoxia-induced apoptosis of MCT cells was aggravated by Mint3 knockdown. Unexpectedly, the additional knockdown of FIH did not suppress the increase in apoptosis by Mint3 knockdown, demonstrating the irrelevance of the FIH/HIF pathway. Therefore, we next focused on nuclear factor (NF)-κB, which has an anti-apoptotic role. Indeed, not only the expression of the inhibitory NF-κB p50 but also the DNA-binding activity of p50/p50 homodimer was increased by knockdown of Mint3 in the TECs, along with the decreased expressions of the NF-κB-targeted anti-apoptotic genes. An increase in NF-κB p50 was also confirmed in Mint3-knockout kidneys. CONCLUSIONS: Mint3 in epithelial cells protects the cells from apoptosis by up-regulating anti-apoptotic effects of NF-κB, leading to fibrosis suppression. This new pathophysiology of tubulointerstitial fibrosis could be a target of future therapy for CKD.

[Interstitial nephritis]. / Interstitielle Nephritis.

Acute interstitial nephritis (AIN) is a rare, often underdiagnosed condition and a common cause of renal failure. Drugs are the leading cause. The underlying pathophysiological condition is often a type IV hypersensitivity reaction. There are also rarer idiopathic forms, which often remain unrecognized. Additionally, the pathophysiological mechanisms are poorly understood, so that only very few promising forms of treatment are available. For some medications the overall risk is low but the side effects are relevant for the clinical routine due to the fact that they are frequently prescribed. In addition, the development of new approaches, such as immunotherapy also leads to side effects that cannot be completely predicted. For many diseases the occurrence of acute kidney injury increases the mortality and morbidity. A potentially irreversible chronic renal failure increases the incidence of further comorbidities and reduces the quality of life. Treatment is difficult and mostly empirical.

Protective role of relaxin in a mouse model of aristolochic acid nephropathy.

BACKGROUND: Aristolochic acid nephropathy (AAN) is a chronic, progressive interstitial nephritis. To date, treatment strategies remain limited. Mounting evidence shows that relaxin (RLX) possesses powerful anti-fibrotic and anti-apoptotic characteristics, therefore, the present study aimed to investigate the possible protective role of RLX in aristolochic acid (AA) induced nephrotoxicity. METHODS: The in vitro cell tests were performed: the embryonic kidney cells 293 were treated with AA-I (40 µg/mL) or with AA-I (40 µg/mL) plus RLX (100 ng/mL) and the cell groups were then tested and the normal 293 cells were set as blank control. In addition, the in vivo animal tests were performed: mice were randomly divided into three groups: a control group injected intraperitoneally with an equal volume of saline every other day for 6 weeks, an AA group injected intraperitoneally with AA-I (5 mg/kg) every other day for 6 weeks, and an AA + RLX group treated with the AA-I for 6 weeks and subsequently received RLX (0.25 mg/kg/day) using an implanted osmotic mini-pump for an additional 2 weeks. 8 weeks post-AA-I, mice were sacrificed for analysis. RESULTS: In the in vivo animal tests, RLX administration prevented increased plasma creatinine and nitrogen levels caused by aristolochic acid as well as alleviated the severity of renal ultrastructural lesions induced by aristolochic acid. Both in the in vitro cell tests and in the in vivo animal tests, Western blotting of the AA-I group showed increased expression of the pro-apoptotic protein genes Bax and the cleaved form of caspase-3, both of which were reversed by RLX. In contrast, the expression of the anti-apoptotic gene Bcl-2 correlated inversely to Bax in RLX treated mice. RLX restored the decreased phosphorylated Akt induced by AA-I. The protein expression of eNOS was also reduced in AA-I treated group compared with control, which was reversed in the presence of RLX. Immunohistochemical staining of the animal tissue revealed that RLX markedly reduced the overexpression of type IV collagen, fibronectin, and alpha-smooth muscle actin in AA-I treated mice. CONCLUSIONS: Our results suggest that RLX alleviates AA-I induced kidney fibrosis by reducing apoptosis and up-regulation the expression of p-Akt.

Chronic Interstitial Nephritis in Agricultural Communities (CINAC) in Sri Lanka.

A significant increase in cases of chronic kidney disease has been observed in the dry zone of Sri Lanka. This unusual chronic kidney disease was first reported in the early 1990s among middle-aged paddy farmers. Considering epidemiologic and histopathologic findings, the disease recently was named chronic interstitial nephritis in agricultural communities (CINAC). Twenty-five years after the first report, CINAC is the most significant public health issue in the paddy farming areas with more than 70,000 estimated patients and many deaths. Histopathologically, this disease is a tubular interstitial nephritis associated with glomerular sclerosis and mild vascular changes. Morphologic and biochemical characteristics of CINAC in Sri Lanka share many similarities with Mesoamerican nephropathy. Certain natural and man-made toxins, heat stress with repeated volume and salt depletion, infections such as hantavirus and leptospirosis, and a genetic origin have been proposed and investigated as possible etiologies, and an association between CINAC and herbicides is widely discussed. Several preventive measures already have been implemented by health authorities in Sri Lanka to minimize nephrotoxin exposure and well hydrate the inhabitants in the disease-endemic region. The impact of these interventions will be watched with anticipation.

5-aminolaevulinic acid (ALA), enhances heme oxygenase (HO)-1 expression and attenuates tubulointerstitial fibrosis and renal apoptosis in chronic cyclosporine nephropathy.

BACKGROUND: Cyclosporine-A (CsA) is an immunosuppressant indicated for various immunological diseases; however, it can induce chronic kidney injury. Oxidative stress and apoptosis play a crucial role in CsA-induced nephrotoxicity. The present study evaluated the protective effect of combining 5-aminolaevulinic acid with iron (5-ALA/SFC), a precursor of heme synthesis, to enhance HO-1 activity against CsA-induced chronic nephrotoxicity. METHODS: Mice were divided into three groups: the control group (using olive oil as a vehicle), CsA-only group, and CsA+5-ALA/SFC group. After 28 days, the mice were sacrificed, and blood and kidney samples were collected. In addition to histological and biochemical examination, the mRNA expression of proinflammatory and profibrotic cytokines was assessed. RESULTS: Renal function in the 5-ALA/SFC treatment group as assessed by the serum creatinine and serum urea nitrogen levels was superior to that of the CsA-only treatment group, demonstrating that 5-ALA/SFC significantly attenuated CsA-induced kidney tissue inflammation, fibrosis, apoptosis, and tubular atrophy, as well as reducing the mRNA level of TNF-α, IL-6, TGF-ß1, and iNOS while increasing HO-1. CONCLUSION: The activity of 5-ALA/SFC has important implications for clarifying the mechanism of HO-1 activity in CsA-induced nephrotoxicity and may provide a favorable basis for clinical therapy.

Peroxidasin and eosinophil peroxidase, but not myeloperoxidase, contribute to renal fibrosis in the murine unilateral ureteral obstruction model.

Renal fibrosis is the pathological hallmark of chronic kidney disease (CKD) and manifests as glomerulosclerosis and tubulointerstitial fibrosis. Reactive oxygen species contribute significantly to renal inflammation and fibrosis, but most research has focused on superoxide and hydrogen peroxide (H2O2). The animal heme peroxidases myeloperoxidase (MPO), eosinophil peroxidase (EPX), and peroxidasin (PXDN) uniquely metabolize H2O2 into highly reactive and destructive hypohalous acids, such as hypobromous and hypochlorous acid. However, the role of these peroxidases and their downstream hypohalous acids in the pathogenesis of renal fibrosis is unclear. Our study defines the contribution of MPO, EPX, and PXDN to renal inflammation and tubulointerstitial fibrosis in the murine unilateral ureteral obstruction (UUO) model. Using a nonspecific inhibitor of animal heme peroxidases and peroxidase-specific knockout mice, we find that loss of EPX or PXDN, but not MPO, reduces renal fibrosis. Furthermore, we demonstrate that eosinophils, the source of EPX, accumulate in the renal interstitium after UUO. These findings point to EPX and PXDN as potential therapeutic targets for renal fibrosis and CKD and suggest that eosinophils modulate the response to renal injury.

Protective effect of cyclosporine on inflammatory injury of renal tubular epithelial cells.

OBJECTIVE: This study aims to explore the protective effect of cyclosporine on inflammation-induced renal tubular epithelial cells and its potential mechanism. MATERIALS AND METHODS: Human kidney-2 (HK-2) cells were induced by transforming growth factor-ß (TGF-ß) for constructing an inflammatory injury model. Cells were then treated with different concentrations of cyclosporine for further investigating the biological functions. Cell viability was detected via cell counting kit-8 assay (CCK-8). The cytotoxicity was detected via lactate dehydrogenase (LDH) release assay. Expression levels of cell damage factors and mammalian target of rapamycin (mTOR) pathway-related genes were detected via polymerase chain reaction (PCR), immunofluorescence and Western blotting, respectively. RESULTS: TGF-ß inhibited the viability of HK-2 cells, increased expressions of tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß) and apoptosis-related genes. Cyclosporine treatment greatly reversed the cell damage on HK-2 cells induced by TGF-ß. Expression levels of mTOR pathway-related genes were downregulated after cyclosporine treatment. CONCLUSIONS: Cyclosporine protects HK-2 cells from inflammatory injury via regulating mTOR pathway.

Protocolos de Vigilancia Centinela de enfermedad renal crónica y manual de registro guatemalteco de diálisis y trasplante renal. No. 12 / Sentinel Surveillance Protocols of chronic kidney disease and manual of Guatemalan dialysis and renal transplantation. No. 12

Estos protocolos están dirigido a personal médico, paramédico y otros profesionales que realizan acciones gerenciales y operativas de vigilancia epidemiológica en los servicios de salud del país, y están divididos en varios tomos para dar a conocer y actualizar la identificación y medidas de control para diversos padecimientos a fin de continuar con el mejoramiento de las capacidades técnicas de los trabajadores de salud, que permita planificar la prestación de servicios con decisiones partiendo de un enfoque epidemiológico comprobado, para responder a los cambios de tendencias epidemiológicas y con ello contribuir al fortalecimiento de prácticas asertivas de la salud pública de nuestro país. Por otra parte, en el documento se afirma que "en el marco de la "Reunión de Alto Nivel sobre Enfermedad Renal Crónica de Causas no Tradicionales en Centroamérica" (ERCnT), celebrada en abril del 2013, los Estados Miembros de Centroamérica y la República Dominicana, que forman parte del Sistema de la Integración Centroamericana (SICA) y la Comisión de Ministros de Salud de Centroamérica y República Dominicana (COMISCA) a través de la "Declaración de San Salvador" reconocen que la enfermedad renal crónica es un problema de salud pública importante en Centroamérica y requiere de una acción urgente."

Tisp40 deficiency limits renal inflammation and promotes tubular cell proliferation in renal ischemia reperfusion injury.

Renal ischemia reperfusion (IR) is a common cause of acute kidney injury (AKI), and no effective treatment is available to date. In our previous studies, we demonstrated that Tisp40 exacerbates tubular cell apoptosis and tubulointerstitial fibrosis after renal IR injury. However, the role of Tisp40 in renal inflammatory responses and tubular cell proliferation during renal IR injury remains unknown. In this study, Tisp40 knockout (KO) and wild-type (WT) mice were induced with or without renal IR injury. For renal IR, bilateral renal pedicels were exposed and clamped to induce 30 min of ischemia. After 48 h of reperfusion, the kidneys were collected for analyses. Results showed that Tisp40 deficiency attenuates neutrophil and macrophage infiltration after renal IR. Consistently, the protein levels of TNF-α and MCP-1 were markedly decreased, and the phosphorylation levels of IκBα and P65 were inhibited in Tisp40-deficient mice than in WT mice in renal IR injury. In addition, compared with WT mice, Tisp40 deficiency significantly increased the expression levels of proliferative cellular nuclear antigen and phosphorylated Erk1/2 after renal IR injury. In conclusion, Tisp40 deficiency limits renal inflammatory responses and promotes tubular cell proliferation in ischemic AKI.

P16 INK4a Deletion Ameliorated Renal Tubulointerstitial Injury in a Stress-induced Premature Senescence Model of Bmi-1 Deficiency.

To determine whether p16 INK4a deletion ameliorated renal tubulointerstitial injury by inhibiting a senescence-associated secretory phenotype (SASP) in Bmi-1-deficient (Bmi-1 -/-) mice, renal phenotypes were compared among 5-week-old Bmi-1 and p16 INK4a double-knockout, and Bmi-1 -/- and wild-type mice. Fifth-passage renal interstitial fibroblasts (RIFs) from the three groups were analyzed for senescence and proliferation. The effect of Bmi-1 deficiency on epithelial-to-mesenchymal transition (EMT) was examined in Bmi-1-knockdown human renal proximal tubular epithelial (HK2) cells, which were treated with concentrated conditioned medium (CM) from the fifth-passage renal interstitial fibroblasts (RIFs) of above three group mice or with exogenous TGF-ß1. Our results demonstrated that p16 INK4a deletion largely rescued renal aging phenotypes caused by Bmi-1 deficiency, including impaired renal structure and function, decreased proliferation, increased apoptosis, senescence and SASP, DNA damage, NF-κB and TGF-ß1/Smad signal activation, inflammatory cell infiltration, and tubulointerstitial fibrosis and tubular atrophy. P16 INK4a deletion also promoted proliferation, reduced senescence and SASP of RIFs and subsequently inhibited EMT of Bmi-1-knockdown HK2 cells. TGF-ß1 further induced the EMT of Bmi-1-knockdown HK2 cells. Thus, p16 INK4a positive senescent cells would be a therapeutic target for preventing renal tubulointerstitial injury.

Tacrolimus and mycophenolate regimen and subclinical tubulo-interstitial inflammation in low immunological risk renal transplants.

The aim was to evaluate the relationship between maintenance immunosuppression, subclinical tubulo-interstitial inflammation and interstitial fibrosis/tubular atrophy (IF/TA) in surveillance biopsies performed in low immunological risk renal transplants at two transplant centers. The Barcelona cohort consisted of 109 early and 66 late biopsies in patients receiving high tacrolimus (TAC-C0 target at 1-year 6-10 ng/ml) and reduced MMF dose (500 mg bid at 1-year). The Oslo cohort consisted of 262 early and 237 late biopsies performed in patients treated with low TAC-C0 (target 3-7 ng/ml) and standard MMF dose (750 mg bid). Subclinical inflammation, adjusted for confounders, was associated with low TAC-C0 in the early (OR: 0.75, 95% CI: 0.61-0.92; P = 0.006) and late biopsies (OR: 0.69, 95% CI: 0.50-0.95; P = 0.023) from Barcelona. In the Oslo cohort, it was associated with low MMF in early biopsies (OR: 0.90, 95% CI: 0.83-0.98; P = 0.0101) and with low TAC-C0 in late biopsies (OR: 0.77, 95% CI: 0.61-0.97; P = 0.0286). MMF dose was significantly reduced in Oslo between early and late biopsies. IF/TA was not associated with TAC-C0 or MMF dose in the multivariate analysis. Our data suggest that in TAC- and MMF-based regimens, TAC-C0 levels are associated with subclinical inflammation in patients receiving reduced MMF dose.

In vivo antitumour potential of camel's milk against hepatocellular carcinoma in rats and its improvement of cisplatin renal side effects.

CONTEXT: Camel milk (CM) is recommended for liver disease patients in Egypt for a strong belief that it has a curative effect. OBJECTIVE: The effect of consumption of CM with or without chemotherapeutic drug cisplatin was evaluated on induced hepatocarcinogenesis in rats. MATERIALS AND METHODS: Wistar male rats (56) were divided into eight groups (7 rats each). Group I was control. Hepatocarcinogenesis was initiated by a single dose of intraperitoneal injection of diethylnitrosamine (DENA) (200 mg/kg BW) and promoted by phenobarbitone (500 ppm) in drinking water in groups V, VI, VII and VIII. Treatment started from 28th till 38th week using CM (5 mL/day) and/or cisplatin (5 mg/kg/3 weeks) in groups II, III IV, VI, VII and VIII. Biochemical analysis, lipid peroxidation and superoxide dismutase (SOD) activity in liver tissue were performed. Histopathology of liver and kidney and immunohistochemistry of placental glutathione-S-transferase (P-GST) in liver were performed and analyzed using image analysis. RESULTS: Albumin concentration and SOD activity were 3.13 ± 0.23 and 311.45 ± 41.71 in group VII (DENA & cisplatin), whereas they were 4.3 ± 0.15 and 540.5 ± 29.94 in group VII (DENA, CM and cisplatin). The mean area of altered hepatocellular foci and P-GST altered foci decreased in group VI (DENA and CM) (1049.6 ± 174.78 and 829.1 ± 261) and group VIII (cisplatin and CM) (1615.12 ± 436 and 543.9 ± 127) compared to group V (DENA only) (4173.74 ± 510.7 and 3169.49 ± 538.61). Cisplatin caused chronic interstitial nephritis, which was slightly alleviated in group VIII (CM and cisplatin). CONCLUSIONS: CM had an antioxidant effect and together with cisplatin managed to decrease hepatocarcinogenesis.

Experience with direct acting anti-viral agents for treating hepatitis C virus infection in renal transplant recipients.

In recent past, direct-acting anti-viral drugs (DAAs) have become the standard of care for the treatment of hepatitis C virus (HCV) infection. However, the experience with the use of these drugs in Indian renal transplant recipients is limited. We retrospectively reviewed our experience with DAA-based treatment for HCV infection in such patients. Between April 2015 and December 2016, six adults (median age 41 [range 34-52] years, male 5; GT1 2, GT3 3, and GT4 1; including three with prior failed interferon-based treatment) had received genotype-guided, DAA-based anti-HCV treatment 1 to 158 (median 15) months after renal transplantation. Of them, four completed the planned 24-week treatment without any significant adverse event. One of them had increase in serum creatinine after 16 weeks of treatment with sofosbuvir and daclatasvir, with acute interstitial nephritis on kidney biopsy; his renal function improved on stopping the drugs. The other patient had preexisting mild renal dysfunction, which worsened after 8 weeks of sofosbuvir-ledipasvir treatment; this did not reverse on stopping treatment. All the six patients achieved undetectable HCV RNA after 4 weeks of treatment and also achieved sustained virologic response, i.e. lack of detectable HCV RNA in serum 12 weeks after stopping treatment. Overall, DAA-based treatment was effective in treating HCV infection in our renal transplant recipients; however, caution and monitoring of renal function during such treatment is advisable in patients who have additional factors that predispose to renal injury.

Reverse osmosis plant maintenance and efficacy in chronic kidney disease endemic region in Sri Lanka.

OBJECTIVE: Chronic Interstitial Nephritis in Agricultural Communities (CINAC) causes major morbidity and mortality for farmers in North-Central province (NCP) of Sri Lanka. To prevent the CINAC, reverse osmosis (RO) plants are established to purify the water and reduce the exposure to possible nephrotoxins through drinking water. We assessed RO plant maintenance and efficacy in NCP. METHODS: We have interviewed 10 RO plant operators on plant establishment, maintenance, usage and funding. We also measured total dissolved solids (TDS in ppm) to assess the efficacy of the RO process. RESULTS: Most RO plants were operated by community-based organizations. They provide clean and sustainable water source for many in the NCP for a nominal fee, which tends to be variable. The RO plant operators carry out RO plant maintenance. However, maintenance procedures and quality management practices tend to vary from an operator to another. RO process itself has the ability to lower the TDS of the water. On average, RO process reduces the TDS to 29 ppm. CONCLUSIONS: The RO process reduces the impurities in water available to many individuals within CINAC endemic regions. However, there variation in maintenance, quality management, and day-to-day care between operators can be a cause for concern. This variability can affect the quality of water produced by RO plant, its maintenance cost and lifespan. Thus, uniform regulation and training is needed to reduce cost of maintenance and increase the efficacy of RO plants.

Renoprotective effects of aliskiren on adenine-induced tubulointerstitial nephropathy: possible underlying mechanisms.

The present study investigated the possible renoprotective effect of direct renin inhibitor (aliskiren) on renal dysfunctions, as well as its underlying mechanisms in rat model of adenine-induced tubulointerstitial nephropathy. Forty male Sprague-Dawley rats were randomized into 4 groups; normal group, aliskiren group (normal rats received 10 mg/kg aliskiren), adenine group (animals received high-adenine diet for 4 weeks and saline for 12 weeks), and adenine + aliskiren group (animals received adenine for 4 weeks and aliskiren 10 mg/kg for 12 weeks). It was found that adenine caused significant decrease in body mass, Hb, HR, serum Ca(2+), eNOS and nrf2 expression, GSH, and catalase in kidney tissues with significant increase in arterial blood pressure (ABP), serum creatinine, BUN, plasma renin activity (PRA), K(+) and P, urinary albumin excretion (UAE), caspase-3, and MDA (lipid peroxidation marker) in kidney tissues compared to normal group (p < 0.05). Administration of aliskiren caused significant improvement in all studied parameters compared to adenine group (p < 0.05). We concluded that aliskiren has renoprotective effect against adenine-induced nephropathy. This might be due to inhibition of PRA, attenuation of oxidative stress, activation of Nrf2 and eNOS genes, and suppression of caspase-3.

Concomitant inhibition of renin angiotensin system and Toll-like receptor 2 attenuates renal injury in unilateral ureteral obstructed mice.

BACKGROUND/AIMS: There has been controversy about the role of Toll-like receptor 2 (TLR2) in renal injury following ureteric obstruction. Although inhibition of the renin angiotensin system (RAS) reduces TLR2 expression in mice, the exact relationship between TLR2 and RAS is not known. The aim of this study was to determine whether the RAS modulates TLR2. METHODS: We used 8-week-old male wild type (WT) and TLR2-knockout (KO) mice on a C57Bl/6 background. Unilateral ureteral obstruction (UUO) was induced by complete ligation of the left ureter. Angiotensin (Ang) II (1,000 ng/kg/min) and the direct renin inhibitor aliskiren (25 mg/kg/day) were administrated to mice using an osmotic minipump. Molecular and histologic evaluations were performed. RESULTS: Ang II infusion increased mRNA expression of TLR2 in WT mouse kidneys (p < 0.05). The expression of renin mRNA in TLR2-KO UUO kidneys was significantly higher than that in WT UUO kidneys (p < 0.05). There were no differences in tissue injury score or mRNA expression of monocyte chemotactic protein 1 (MCP-1), osteopontin (OPN), or transforming growth factor ß (TGF-ß) between TLR2-KO UUO and WT UUO kidneys. However, aliskiren decreased the tissue injury score and mRNA expression of TLR2, MCP-1, OPN, and TGF-ß in WT UUO kidneys (p < 0.05). Aliskiren-treated TLR2-KO UUO kidneys showed less kidney injury than aliskiren-treated WT UUO kidneys. CONCLUSIONS: TLR2 deletion induced activation of the RAS in UUO kidneys. Moreover, inhibition of both RAS and TLR2 had an additive ameliorative effect on UUO injury of the kidney.

The protective effect of neutralizing high-mobility group box1 against chronic cyclosporine nephrotoxicity in mice.

BACKGROUND: High-mobility group box1 (HMGB1) is known to be involved in innate immune response through interaction with receptor for advanced glycation end products (RAGE) and toll-like receptors (TLRs), besides its proper role within the nucleus. Immunological pathways, including TLR signaling, are also involved in chronic cyclosporine (CsA) nephrotoxicity. This study was designed to determine whether neutralizing HMGB1 prevents chronic CsA nephrotoxicity. METHODS: Chronic CsA nephrotoxicity was induced by CsA subcutaneous injection daily for 4weeks under salt-depletion in mice. Anti-HMGB1 neutralizing antibody for HMGB1 blockade (600mcg/mouse) was administered weekly to mice in the anti-HMGB1 treatment group. The effects of HMGB1 neutralization were evaluated in terms of renal function as well as histological and immunopathological examination. RESULTS: Anti-HMGB1 administration prevented the increases in serum creatinine and 24h albuminuria and the decrease in creatinine clearance associated with CsA treatment. Increased tubulointerstitial fibrosis and transforming growth factor (TGF)-ß immunohistochemical staining associated with CsA treatment were also prevented by anti-HMGB1 administration. Anti-HMGB1 administration prevented the activation of the TLR4 signaling pathway, which resulted in the reduction of nuclear factor kappa B (NF-κB) expression. In cultured tubular cells, anti-HMGB1 pretreatment also prevented the increases in fibronectin and collagen IV levels associated with CsA treatment. CONCLUSIONS: Neutralizing HMGB1 with an anti-HMGB1 antibody ameliorated chronic CsA nephrotoxicity via inhibition of the TLR4 signaling pathway. Our study suggests that HMGB1 blockade can be beneficial for increasing allograft survival in renal transplant recipients by protecting against calcineurin inhibitor-induced nephrotoxicity.