Atrial natriuretic peptide attenuates kidney–lung crosstalk in kidney injury

Background

Renal ischemia–reperfusion injury (IRI) is a common cause of acute kidney injury after cardiovascular surgery, which in turn deteriorates oxygenation. Atrial natriuretic peptide (ANP) has natriuretic, diuretic, and anti-inflammatory effects. To elucidate whether renal IRI induces inflammation in the kidney and lung and ANP attenuates kidney–lung crosstalk.

Materials and methods

The rats were anesthetized, tracheostomized, mechanically ventilated, and randomized to four groups: saline + IRI (n = 12), ANP + IRI (n = 12), ANP + sham (n = 6), and saline + sham (n = 6). Saline (6 mL/kg/h) or ANP (0.2 μg/kg/min) at the rate of 6 mL/kg/h was started 5 min before clamping, respectively. Renal IRI was induced by clamping the left renal pedicle for 30 min. The hemodynamics, arterial blood gases, and plasma concentrations of creatinine and lactate were measured at baseline and 1, 2, and 3 h after declamping. Lung wet-to-dry ratio was measured. The mRNA expression of tumor necrosis factor (TNF)-α, interleukin (IL) 1β, and IL-6 and histologic localization of TNF-α in the kidney and lung were measured.

Results

Renal IRI induced metabolic acidosis, pulmonary edema, increases in plasma concentrations of creatinine and lactate, and augmentation of the cytokine mRNA expression and histologic localization of TNF-α in the kidney and Renal IRI induced lung. ANP prevented IRI-induced metabolic acidosis, pulmonary edema, increases in creatinine, lactate, and the cytokine mRNA expression, attenuated histologic localization of TNF-α in the kidney and lung, and increased oxygenation.

Conclusions

ANP has renoprotective and anti-inflammatory effects on the kidney and lung in a rat model of renal IRI, suggesting that ANP attenuates kidney–lung crosstalk.     

L-Carnitine Protects Against Cyclosporine-Induced Pancreatic and Renal Injury in Rats

Background

L-carnitine has protective effects against various types of injury. This study was designed to evaluate the beneficial effects of L-carnitine on pancreatic and renal injuries caused by cyclosporine (CsA).

Methods

Rats maintained on a low sodium diet were given vehicle (olive oil, 1 mL/kg/d), CsA (15 mg/kg/d), L-carnitine (50 or 200 mg/kg/d), or a combination of CsA and L-carnitine for 4 weeks. The impact of L-carnitine on pancreatic injury was assessed by blood glucose levels, plasma insulin concentrations, and hemoglobulin A1c (HbA1c). In addition, the protective effects of L-carnitine against CsA-induced kidney injury were evaluated in terms of renal function, histopathology (inflammatory cell influx and tubulointerstitial fibrosis), oxidative stress (8-hydroxy 2′-deoxyguanosine, 8-OHdG), transforming growth factor-betal (TGF-β1), apoptosis (caspase-3), and autophagy (LC3-II).

Results

CsA treatment caused diabetes, renal dysfunction, tubulointerstitial inflammation (ED-1-positive cells), and fibrosis, which were accompanied by an increase in 8-OHdG production and upregulation of TGF-β1, caspase-3, and LC3-II. Concomitant administration of L-carnitine increased plasma insulin concentrations, decreasing plasma glucose and HbA1c levels. In the kidney, L-carnitine induced dose-dependent improvement of renal function, inflammation, and fibrosis in parallel with suppression of the expression of TGF-β1 and 8-OHdG. Furthermore, the administration of L-carnitine at a high dose inhibited the expression of caspase-3 and LC3-II.

Conclusion

These findings suggest that L-carnitine has a protective effect against CsA-induced pancreatic and renal injuries.     

Splenectomy Attenuates the Course of Kidney Ischemia-Reperfusion Injury in Rats

Introduction

Renal ischemia-reperfusion injury (IRI) initiates inflammatory response with synthesis of free oxygen radicals, chemokines, and cytokines which attract neutrophils and monocytes, which then differentiate into macrophages and dendritic cells, activating adaptive immune response. The spleen is the main source of both monocytes and lymphocytes. The aim of this study was to assess whether splenectomy performed before or upon IRI affects post-ischemic and long-term renal function.

Methods

Two weeks after right nephrectomy, the left kidney pedicle was clamped for 45 minutes in 24 rats. After the clip insertion, the spleen was removed in 12 animals and the remaining 12 rats underwent sham splenectomy. In the second experiment, splenectomy (n = 9) or sham procedure (n = 9) was performed simultaneously with right nephrectomy, 2 weeks before left kidney ischemia. The excretory function of the kidney was evaluated 48 hours and 7 days after ischemia. In the experimental model of chronic renal failure, 14 days before right nephrectomy, the prolonged 90-minute ischemia was induced in 32 rats with simultaneous splenectomy (n = 16) or sham procedure (n = 16). In long-term observation, the renal function and mortality rate was evaluated.

Results

Kidney function preservation was superior in rats that underwent splenectomy together with renal ischemia when compared to controls. This was further expressed with a 2 times lower mortality rate in splenectomized animals in 6 months observation after prolonged renal ischemia. Renoprotective effect was not observed when splenectomy was performed 2 weeks before IRI.

Conclusions

The results suggest a detrimental influence of the spleen on the development of renal IRI.     

Urinary Apolipoprotein M Could Be Used as a Biomarker of Acute Renal Injury: An Ischemia-Reperfusion Injury Model of Kidney in Rat

Background

It has been well documented that apolipoprotein M (apoM) is principally expressed in hepatocytes as well as renal tubular epithelial cells. The importance of apoM in the kidney is unknown. In the present study we examined urinary any apoM after short-term ischemia-reperfusion injury (IRI) of kidney in a rat model.

Methods

The kidneys of 11 male Sprague-Dawley rats were rendered ischemic for 45 minutes followed by different intervals of reperfusion. Serum and urine apoM concentrations were determined using a dot-blot analysis with specific rabbit anti-human apoM antibodies that cross-react with rat apoM. Serum concentrations of blood urea nitrogen (BUN) and creatinine (Cr) were determined using standard clinical automated analyses.

Results

BUN was significantly elevated after 45 minutes of ischemia followed by 24 hours of reperfusion; serum Cr concentrations were also significantly increased at 6 and 24 hours of reperfusion. Interestingly, similar to BUN and Cr, serum apoM concentrations were significantly increased after ischemia for 45 minutes alone and after 2 hours of reperfusion. Urinary apoM concentrations were obviously increased after 2 h as well as 6 hours of reperfusion.

Conclusion

apoM showed characteristics of an acute-phase reactive protein; its occurrence in urine may be considered to be a biomarker of acute renal injury.     

Pioglitazone protects against renal ischemia-reperfusion injury by enhancing antioxidant capacity

Background

In our previous study, we showed that pioglitazone exerts protective effects on renal ischemia-reperfusion injury (IRI) in mice by abrogating renal cell apoptosis. Oxidative stress due to excessive production of reactive oxygen species and subsequent lipid peroxidation plays a critical role in renal IRI. The purpose of the current study is to demonstrate the effect of pioglitazone on renal IRI by modulation of oxidative stress.

Materials and methods

IRI was induced by bilateral renal ischemia for 45 min followed by reperfusion. Thirty healthy male Balb/c mice were randomly assigned to one of the following groups: phosphate buffer solution (PBS) + IRI, pioglitazone + IRI, PBS + sham IRI, pioglitazone + sham IRI. Kidney function tests and kidney antioxidant activities were determined 24 h after reperfusion.

Results

Pretreatment with pioglitazone produced reduction in serum levels of blood urea nitrogen and creatinine caused by IRI. Pretreatment with pioglitazone before IRI resulted in a higher level of kidney enzymatic activities of superoxide dismutase, glutathione, catalase, and total antioxidant capacity than in the PBS-pretreated IRI group.

Conclusions

Our results indicate that pioglitazone can provide protection for kidneys against IRI by enhancing antioxidant capacity. Therefore, pioglitazone could be a potential therapeutic approach to prevent renal IRI relevant to various clinical conditions.     

Involvement of peroxisome proliferator–activated receptor gamma in vitamin D–mediated protection against acute kidney injury in rats

Background

Vitamin D has been reported as renoprotective agents in various studies. Recently, a few in vitro studies highlighted cross talk between vitamin D and peroxisome proliferator–activated receptor gamma (PPAR-γ). The present study investigated the activation of PPAR-γ as novel mechanism in vitamin D–mediated protection against ischemia reperfusion–induced acute kidney injury (AKI) in rats.

Materials and methods

The AKI was induced by clamping renal pedicles for 40 min followed by reperfusion for 24 h. The AKI was assessed by measuring creatinine clearance, serum urea, uric acid level, and lactate dehydrogenase activity. Moreover, serum potassium, calcium level, fractional excretion of sodium, and microproteinuria were measured in rats. The oxidative stress in renal tissues was assessed by quantification of thiobarbituric acid–reactive substances, superoxide anion generation, reduced glutathione level, and catalase and myeloperoxidase activities. The hematoxylin-eosin staining was carried out to observe histopathologic changes in renal tissues. Vitamin D (0.25, 0.5, and 1 μg/kg) was administered for 7 d before subjecting rats to renal ischemia reperfusion injury (IRI).

Results

The renal IRI in rats induced significant changes in serum, urinary, and oxidative stress parameters in renal tissues. Moreover, hematoxylin-eosin staining revealed marked damage produced by IRI in renal tissues. The administration of vitamin D at 0.5 μg/kg dose afforded maximum protection against renal IRI. The prior treatment with PPAR-γ antagonist bisphenol A diglycidyl ether significantly attenuated protective effect of vitamin D, thus confirming involvement of PPAR-γ in vitamin D–mediated renoprotection.

Conclusions

It is concluded that activation of PPAR-γ significantly contributes toward vitamin D–mediated protection against ischemia reperfusion–induced AKI.     

Chronic Allograft Nephropathy in Rats Is Improved by the Intervention of Rhein

Aim

In this study, we investigated the therapeutic efficacy and potential mechanisms of rhein to mitigate chronic allograft nephropathy (CAN) in rats.

Materials and Methods

Fisher rat donors and Lewis rat recipients were used to establish the CAN model. Thirty rats with transplanted kidneys were randomly divided into two groups: 16 untreated and 14 rhein = treated rats. Five Lewis rat controls underwent removal of their right kidneys. The Intervention group was administered rhein oral solution (100 mg kg^-1 d^-1) by gavage after transplantation. The untreated and control groups were given 0.5% sodium carboxymethyl cellulose. Blood and urine samples were collected at 4, 8, and 16 weeks to examine renal function and total urine protein. Half of the rats in each group were sacrifice at 8 or 16 weeks to examine renal pathology. Immunohistochemical examination and real-time polymerase chain reaction of renal tissues were performed to detect expressions of transforming growth-β1(TGF-β1), hepatic growth factor (HGF), bone morphogenetic protein 7 (BMP7), frobronectin, and collgen IV.

Results

Rhein improved renal function and significantly reduced renal fibrosis and interstitial inflammation. The levels of BMP7 and HGF were significantly elevated in the renal tissues of the rhein intervention group. In the meantime, fibronectin and collagen IV were decreased in the extracellular matrix. The expression of TGF-β1 was similar between these two groups.

Conclusion

Rhein improved renal function and reduced renal fibrosis and interstitial inflammation by inducing production of HGF and BMP7.     

Immune Tolerance of Amniotic Fluid Stem Cell–Induced Rat Kidney Graft and Influences on Oxidative Stress

Objective

This study aimed to use amniotic fluid stem cells of donors to induce immune tolerance of heterogenous rat kidney graft for investigating the formation mechanism of immune tolerance.

Methods

With Wistar rats as donors and Sprague-Dawley (SD) rats as receptors, the heterogenous kidney graft animal model was established, and amniotic fluid stem cells of Wistar rats were isolated and cultured. Moreover, 40 SD rats were randomly divided into 4 groups. Creatinine (Cr), blood urea nitrogen (BUN), interleukin (IL) 2, interferon (IFN) γ, and oxidative stress levels in serum were detected, flow cytometry was used to detect changes of CD4 and CD8 cells, and quantitative changes of urinary protein and pathologic changes of transplanted kidney were observed.

Results

BUN, Cr, IL-2, IFN-γ, and oxidative stress levels and urinary protein quantity in rat serum of the test group were significantly lower than those of the control group, creatinine clearance rate was significantly higher than that of the control group, and renal pathologic injury extent was significantly milder than that of the control group.

Conclusions

Amniotic fluid stem cells can induce immune tolerance of rat kidney graft and inhibit oxidative stress level, improve kidney function, and alleviate kidney injury.     

Pretreatment with hydrogen-rich saline reduces the damage caused by glycerol-induced rhabdomyolysis and acute kidney injury in rats

Background

Rhabdomyolysis is a leading cause of acute kidney injury. The pathophysiological process involves oxidative stress and inflammation. Hydrogen-rich saline (HRS) is an antioxidant and anti-inflammatory. This study explored the protective effect of pretreatment with HRS on the development of glycerol-induced rhabdomyolysis acute kidney injury.

Materials and methods

Forty-eight rats were randomly divided into four equal groups. Group 1 served as the control, group 2 was given 50% glycerol (10 mL/kg, intramuscular), group 3 was given glycerol after 7 d pretreatment with high dose HRS (10 mL/kg/d, intraperitoneal), and group 4 was given glycerol after 7 d pretreatment with low dose HRS (5 mL/kg/d, intraperitoneal). Renal health was monitored by serum creatinine (Cr), urea, and histologic analysis; rhabdomyolysis was monitored by creatine kinase (CK) levels; and oxidative stress was monitored by kidney tissue reactive oxygen species (ROS), malondialdehyde, 8-hydroxydeoxyguanosine (8-OH-dG), superoxide dismutase (SOD), and glutathione peroxidase (GSH-PX) levels. Inflammation was monitored by interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-α) evaluation.

Results

Glycerol administration resulted in an increase in the mean histologic damage score, serum Cr, urea and CK, kidney tissue ROS, malondialdehyde, 8-OH-dG, GSH-PX, IL-6, and TNF-α, and a decrease in kidney tissue superoxide dismutase activity. All these factors were significantly improved by both doses of HRS, but the mean histologic damage score, urea, Cr, CK, ROS, 8-OH-dG, GSH-PX, IL-6, and TNF-α for the high dose HRS treatment group were even lower.

Conclusions

Pretreatment by HRS ameliorated renal dysfunction in glycerol-induced rhabdomyolysis by inhibiting oxidative stress and the inflammatory response.     

Thrombomodulin Administration Attenuates Ischemia-Reperfusion Injury of the Remnant Liver After 70% Hepatectomy in Rats: Simulated Model of Small-for-size Graft in Living Donor Liver Transplantation

Background

Hepatic ischemia-reperfusion injury (IRI) is a serious complication affecting liver function and postoperative course after liver transplantation. Thrombomodulin (TM) has been known to have anticoagulant and anti-inflammatory activities exerting a cytoprotective effect. We evaluated the cytoprotective effect of recombinant human soluble TM (rhsTM) on the remnant liver exposed to IRI after 70% hepatectomy in rats, which was the simulated model of small-for-size graft in living donor liver transplantation.

Materials and Methods

A Wistar rat underwent 70% hepatectomy followed by 20-minute IRI for the remnant liver. rhsTM (1 mg/kg) (TM group) or saline (control group) was intravenously administered 30 minutes before operation.

Results

Alanine aminotransaminase levels were more significantly decreased during the 24 hours after operation in the TM group than in control group, especially at 6 hours. Intrahepatic infiltration of macrophages/monocytes (ED-1 immunohistochemical staining) at 6 hours was significantly decreased in the TM group compared to the control group. The number of proliferating cell nuclear antigen−positive cells at 12 hours (hepatocyte proliferation) was significantly higher in the TM group than in the control group; although liver weight 7 days after operation did not differ between the two groups. Hepatocyte apoptosis (terminal deoxynucleotidyl transferase–mediated deoxyuridine triphosphate nick-end labeling, also known as TUNEL assay) at 24 hours was more significantly diminished in the TM group than in the control group.

Conclusion

These results suggest that rshTM attenuates hepatocyte injury through its anti-inflammatory effect, and promotes hepatocyte proliferation in the reduced-size liver exposed to hepatic IRI.     

Nephroprotective Effect of Pentoxifylline in Renal Ischemia–Reperfusion in Rat Depends on the Timing of Its Administration

Background

Renal ischemia–reperfusion injury (IRI) induces inflammatory reaction damaging kidney. Pentoxifylline (PTX) given before IRI attenuates inflammation and prevents ischemic acute kidney injury (iAKI). Given that in clinical settings IRI is not always predictable, we aimed to assess whether PTX administration during or shortly after IRI affects the course of iAKI in the rat.

Methods

In 58 male 10-week-old Sprague-Dawley rats, 14 days after right nephrectomy, a 45-minute clamping of solitary renal pedicle was conducted. PTX 100 mg/kg body weight or 0.9% NaCl 1 mL were given subcutaneously either 60 minutes before renal ischemia, 1 minute into ischemia, or 60 minutes after clamp release. Creatinine clearance (Cl_Cr; mL/min/kg body weight), fractional excretions of sodium (FE_Na [%]) and potassium (FE_K [%]), and urine protein/Cl_Cr ratio (U_prot/Cl_Cr [mg/1 mL Cl_Cr]) at 48 hours after IRI were compared between PTX-treated animals and respective controls (Mann-Whitney U test).

Results

Kidney function was improved in rats given PTX before IRI compared with controls: Cl_Cr 2.10 ± 0.44 versus 1.03 ± 0.18; FE_Na 0.16 ± 0.12 versus 0.84 ± 0.55; FE_K 40.3 ± 13.0 versus 75.5 ± 17.9, respectively (all P < .001). There was no difference in proteinuria: U_prot/Cl_Cr 0.004 ± 0.002 versus 0.004 ± 0.002. Conversely, the analyzed parameters did not differ between animals administered PTX during IRI and controls: Cl_Cr 0.42 ± 0.34 versus 0.73 ± 0.43; FE_Na 2.98 ± 2.71 versus 3.16 ± 3.05; FE_K 280.1 ± 155.7 versus 206.2 ± 154.1; and U_prot/Cl_Cr 0.031 ± 0.029 versus 0.029 ± 0.031, respectively, nor between rats given PTX after IRI and controls: Cl_Cr 0.29 ± 0.38 versus 0.40 ± 0.47; FE_Na 4.25 ± 3.55 versus 3.80 ± 3.94; FE_K 284.9 ± 117.5 versus 243.0 ± 150.6; and U_prot/Cl_Cr 0.044 ± 0.018 versus 0.055 ± 0.061, respectively.

Conclusions

PTX given only before, and not at the time of renal ischemia or after reperfusion, alleviates subsequent iAKI in the rat. This implicates usefulness of PTX in the clinical settings of expected renal ischemia, like kidney transplantation, and suggests potential benefits of PTX in peritransplant period foremost with donor pretreatment.     

Penehyclidine hydrochloride ameliorates renal ischemia–reperfusion injury in rats

Background

Renal ischemia–reperfusion (I/R) injury is a major cause of acute kidney failure by mechanisms that involve oxidative stress, inflammation, and apoptosis. Penehyclidine hydrochloride (PHC), a selective anticholinergic agent, possesses anti-inflammatory, antioxidative stress, and antiapoptotic effects. Therefore, we investigated the ability of PHC to ameliorate renal I/R injury in Sprague–Dawley rats.

Materials and methods

Rats were randomly assigned to three groups (35 rats per group): sham operated, saline-treated I/R, and PHC-treated I/R. After removing the right kidney, renal I/R injury was induced by clamping the left renal artery for 45 min followed by reperfusion. The rats were administered PHC (0.45 mg/kg, intravenously) or saline 30 min before renal ischemia. The blood and kidneys were harvested at 1, 3, 6, 12, or 24 h after reperfusion. Renal function and histologic changes were assessed. Markers of oxidative stress, inflammation, and apoptosis in the kidneys were also measured.

Results

PHC treatment significantly attenuated renal dysfunction and histologic damage caused by I/R injury. The treatment also decreased malondialdehyde level and attenuated the reduction in superoxide dismutase activity in the kidney. Moreover, the levels of activated p38 mitogen-activated protein kinase, nuclear factor kappa B, and caspase 3 were lower in the PHC-treated animals.

Conclusions

PHC protected rat kidneys from I/R injury by attenuating oxidative stress, inflammatory response, and apoptosis. Thus, PHC may represent a novel practical strategy for the treatment of renal I/R injury.     

Analysis of Histologic Changes During Early Rejection After Renal Transplantation by Performing Protocol Biopsy at 1 Year After Kidney Transplantation

Background

In this retrospective study, we analyzed histologic changes identified through protocol biopsy (PB) at 1 year after kidney transplantation (KT). We focused on the pathologic changes observed in patients with a history of treatment for graft rejection within 1 year of transplantation.

Methods

Between January 2008 and December 2011, 56 patients underwent KT at our center. We assessed the histologic findings observed at 1 year after renal transplantation using the Banff 2007 classification. At our center, PBs are performed immediately after or at 1 hour after transplantation, and at 1 year after KT. PBs were performed in 39 patients; PBs could not be performed in 17 patients because of various causes. Of the 39 patients, 29 stabilized without clinical rejection and without treatment (the NTx group); 10 patients showed pathologic changes or clinical rejection after steroid pulse therapy within 1 year (the Tx group). We compared these 2 groups with respect to baseline data, renal function, and pathologic scores.

Results

The interstitial fibrosis (“ci”) score, according to the Banff classification, was significantly greater in the NTx group (0.89) than in the Tx group (0.50) at 1 year after transplantation.

Conclusions

The currently applied early steroid withdrawal regimen may be not be ideal for preventing pathologic changes occurring after KT. In addition to the PB performed 1 year after KT, PB should be performed within 1 year of renal transplantation to identify early signs of rejection and to provide access to appropriate treatment regimes.     

The Impact of Time-Zero Biopsy on Early Graft Outcomes After Living Donor Kidney Transplantation

Background

In contrast with deceased donor transplantation, the clinical significance of pathologic findings in time-zero biopsies after living donor kidney transplantation are rarely reported, due to the expectation that histologic findings and renal function are normal. The aim of this study was to identify subclinical pathologic findings in living donors and examine the effect on early graft renal function.

Methods

Between December 2006 and July 2011, 146 living-donor kidney transplant recipients were enrolled in this study. We retrospectively analyzed donor and recipient-related clinical parameters, and post-transplant 6 months and 1 year estimated glomerular filtration rate (eGFR) as early graft renal function. Time-zero biopsies were evaluated using the 2007 Banff criteria.

Results

Most abnormal histologic findings were of mild degree as determined by Banff scores. Global glomerulosclerosis (GS, 35.6%), tubular atrophy (CT, 36.3%), interstitial fibrosis (CI, 20.5%), vascular fibrous intimal thickening (CV, 4.1%), arteriolar hyaline thickening (AH, 14.4%), interstitial inflammation (I, 3.4%) were pathologic findings in time-zero biopsies. The univariate analysis revealed that donor age and gender were significantly associated with eGFR at post-transplant 6 months and at 1 year (P < .05). Furthermore, GS and CT were significantly associated with early graft renal function (P < .05). However, multivariate linear regression analysis showed only donor age was significantly associated with early graft renal function (P = .001).

Conclusion

A mild degree of subclinical, pathologic findings on time-zero biopsy did not affect early graft renal function in living-donor kidney transplantation.     

Effects of Immunosuppressive Drugs on Rat Renal Ischemia Reperfusion Injury

Introduction

Recent evidence has demonstrated that the immune response and, more specifically, lymphocytes (T and B) and dendritic cells participate as mediators of renal ischemia reperfusion injury (IRI). The aim of this study was, therefore, to evaluate the effect of various immunosuppressive drugs with known activity to prevent IRI among rats undergoing a scheme that is potentially applicable in the clinic.

Methods

Male Sprague-Dawley rats (200-300 g) underwent 60 minutes of ischemia by renal artery clamping and contralateral nephrectomy. The experimental groups (n = 6-7) were as follows: I, Sham; II, Control; III, Rapamycin (R; 1 mg/kg); IV, Methylprednisolone (M; 15 mg/kg); V, Vitamin D3 (VD3; 2 μg/kg); VI, VD3 (1 μg/kg); and VII, M (15 mg/kg) + R (1 mg/kg). Each drug was administered in 2 doses at 6 hours and 1 hour before surgery. Creatinine (Cr) was determined on days 0.1, 2, 3, 5, and 7, and Cr clearance was determined on days 3 and 7. At 7 days nephrectomy was performed to obtain samples for histology to evaluate the degree of acute tubular necrosis.

Results

Mortality from renal insufficiency was between 0 and 33%, except in group V (66%; 4/6; P = .01). Kidney function was similar to controls in all groups except for creatinine at 7 days between group VI (VD3) and control (1.05 vs 0.65; P < .05) but no difference in Cr clearance. Histologically moderate to severe renal damage was greater in groups V and VI (VD3) than controls (P = .04).

Conclusion

We observed that none of the drugs conferred protection against IRI in a time setting relevant to kidney transplantation. Controversy exists regarding R, because some prior studies have shown a deleterious effect on IRI injury, although we did not observe any deleterious effect.     

Exendin-4 ameliorates renal ischemia-reperfusion injury in the rat

Background

Glucagon-like peptide-1 receptor (GLP-1R) activation exerts protective effects against reactive oxygen species by inducing the oxidative defense gene heme oxygenase-1 (HO-1), and provides protection in mice against transient focal cerebral ischemia and ischemia-reperfusion injury in the rat heart. GLP-1R is also expressed in the kidney, but it is unknown whether GLP-1R activation is able to protect against ischemia-reperfusion injury in the rat kidney.

Materials and methods

We used a rat model of renal ischemia-reperfusion injury. The rats were pretreated with the GLP-1R agonist, exendin-4 before reperfusion. We used real-time polymerase chain reaction to evaluate expression of the oxidative defense gene HO-1 and Western blot analysis for HO-1 and GLP-1R. Renal function was assessed at baseline and 24 and 72 h after reperfusion. The kidneys were processed for histologic and morphometric analysis, caspase-3, and ED1 immunohistochemistry at 72 h. The degree of apoptosis of the renal tubular cells was determined using terminal deoxynucleotidyl transferase deoxyuridine triphosphate-biotin nick end labeling assays.

Results

Exendin-4 pretreatment resulted in GLP-1R activation and upregulation of HO-1. Preconditional activation of GLP-1R significantly improved the serum creatinine levels compared with vehicle (P < 0.05). Furthermore, tissue injury, caspase-3 and ED1 expression, and apoptosis were less severe, as quantified by application of a standardized histologic scoring system in a blinded manner.

Conclusions

These results have demonstrated that preconditional activation of the GLP-1R with exendin-4 in the kidney significantly protected against ischemia-reperfusion injury in rats by increasing HO-1 expression.     

Remote ischemic conditioning enhanced the early recovery of renal function in recipients after kidney transplantation: a randomized controlled trial

Background

To investigate whether remote ischemic conditioning (RIC) can attenuate ischemic reperfusion injury (IRI) in recipients after kidney transplantation using donation after cardiac death.

Methods

Forty-eight recipients referred for kidney transplantation were recruited. The paired recipients who received the kidneys from the same donor were randomly assigned (one received RIC and the other did not). RIC was induced by three 5-min cycles of brief repetitive ischemia and reperfusion by clamping the exposed external iliac artery. Blood samples were withdrawn at hour 2, hour 12, days 1–7, day 14, and day 30 to measure serum creatinine level and estimated glomerular filtration rate after transplantation. Urine samples were collected at hours 2, 12, 24, and 48 to measure urine neutrophil gelatinase–associated lipocalin after transplantation. Renal tissues were obtained at 30 min for histologic changes after transplantation.

Results

There were no significant differences in clinical characteristics of the recipients and donors between RIC and control groups. The serum creatinine level was lower in the RIC group compared with that of the control group (12 h, days 1–14, P < 0.05; other P > 0.05); the estimated glomerular filtration rate was higher in the RIC group compared with that of the control group (12 h, days 1–14, P < 0.05; other P > 0.05); urine neutrophil gelatinase–associated lipocalin, an early marker of IRI, was lower in the RIC group at hours 2, 12, 24, and 48 (2 h, 48 h, P > 0.05; 12 h, 24 h, P < 0.05) compared with that of the control group. The graft pathology showed no differences between RIC and control groups.

Conclusions

RIC enhanced the early recovery of renal function in recipients after kidney transplantation. Our results provide a novel potential approach to attenuate transplantation-associated IRI.     

染料木黄酮在减轻肾间质纤维化中的作用

目的 探讨染料木黄酮(Genistein)在减轻单侧输尿管结扎模型(UUO)诱导肾间质纤维化中的作用及可能机制.方法 将30只SD大鼠随机分为5组,A组:假手术+DMSO 1 ml/d×14 d;B组:假手术+Genistein每日20 mg/ks体重×14 d;C组:UUO+DMSO 1 ml/d×14 d;D组:UUO+Genistein 5mg/kg体重每日×14d;E组:UUO+Genistein 20mg/kg体重每日×14d.术后14d比较各组大鼠左/右肾重量和长度的比值;酶联免疫吸附实验(ELISA)法检测血清INF-y和TGFa1表达;病理观察肾小管扩张和肾间质增生的程度,免疫组织化学观察肾脏á-SMA和ED-1表达.结果 C、D、E组左/右肾重量及长度比值均明显高于A、B组,但E组左/右肾重量及长度比值、血清TGF-a1及INF-y浓度、肾小管扩张分数和肾小管容量分数、á-SMA和ED-1的表达均低于C组.结论 染料木黄酮可明显降低由单侧输尿管结扎模型所导致的肾间质纤维化的病理改变,其可能机制是染料木黄酮抑制TGF-a1及INF-y的表达,从而抑制肾小管上皮细胞向成纤维细胞转化.     

Transplantation of bone marrow–derived mesenchymal stem cells after regional hepatic irradiation ameliorates thioacetamide-induced liver fibrosis in rats

Background

Recent studies have demonstrated that bone marrow–derived mesenchymal stem cells (BM-MSCs) can potentially revert liver fibrosis, but it is not known if preparative hepatic irradiation (HIR) contributes to the therapeutic effect of transplanted BM-MSCs. In this study, we investigate the effects of HIR on transplanted BM-MSCs in cirrhotic rats and the underlying mechanism by which mesenchymal stem cells (MSCs) relieve liver fibrosis.

Materials and methods

The BM-MSCs from male rats were labeled with CM-Dil and injected via portal vein into two groups of thioacetamide-induced cirrhotic rats, and the controls were injected with the same volume of saline. The right hemiliver of one cirrhotic rat group was irradiated (15 Gy) 4 d before transplantation. Liver function tests and histologic experiments were performed, and the liver population of BM-MSCs was estimated.

Results

The transplantation of MSCs alleviated liver fibrosis and reduced expression of transforming growth factor-β1, Smad2, collagen type Ⅰ, and α-SMA. HIR preconditioning promoted homing and repopulation of MSCs and resulted in better treatment outcomes.

Conclusions

HIR preconditioning enhances the effect of BM-MSCs in improving thioacetamide-induced liver fibrosis in rats by promoting their homing and repopulation. BM-MSCs may function by inhibiting transforming growth factor-β1-Smad signaling pathway in the liver.