Jianyong Yin

Limb ischemic preconditioning protects against contrast-induced nephropathy via renalase

Clinical trials shows that remote ischemic preconditioning (IPC) can protect against contrast induced nephropathy (CIN) in risky patients, however, the exact mechanism is unclear. In this study, we explored whether renalase, an amine oxidase that has been previously shown to mediate reno-protection by local IPC, would also mediate the same effect elicited by remote IPC in animal model. Limb IPC was performed for 24 h followed by induction of CIN. Our results indicated that limb IPC prevented renal function decline, attenuated tubular damage and reduced oxidative stress and inflammation in the kidney. All those beneficial effects were abolished by silencing of renalase with siRNA. This suggests that similar to local IPC, renalase is also critically involved in limb IPC-elicited reno-protection. Mechanistic studies showed that limb IPC increased TNFα levels in the muscle and blood, and up-regulated renalase and phosphorylated IκBα expression in the kidney. Pretreatment with TNFα antagonist or NF-κB inhibitor, largely blocked renalase expression. Besides, TNFα preconditioning increased expression of renal renalase in vivo and in vitro, and attenuated H2O2 induced apoptosis in renal tubular cells. Collectively, our results suggest that limb IPC-induced reno-protection in CIN is dependent on increased renalase expression via activation of the TNFα/NF-κB pathway.

Sulodexide Protects Contrast-Induced Nephropathy in Sprague-Dawley Rats.

Background: Sulodexide is a powerful antithrombin agent with reno-protective property. However, whether it has beneficial effects on Contrast-Induced Nephropathy (CIN) remained elusive. In the current study, we evaluated the therapeutic effects of Sulodexide on CIN and investigated the potential mechanisms. Methods: CIN model was induced by intravenous injection of indomethacin, followed by Ioversol and L-NAME. Sprague-Dawley rats were divided into 4 groups: control group, CIN group, CIN+vehicle group (CIN rats pretreated with vehicle) and CIN+ Sulodexide (CIN rats pretreated with Sulodexide). Sulodexide or an equivalent volume of vehicle was intravenously delivered 30 min before the induction of CIN. All the animals were sacrificed at 24h after CIN and tissues were harvested to evaluate renal injury, kidney oxidative stress and apoptosis levels. Plasma antithrombin III (ATIII) activities were also measured. Results: Compared to the untreated CIN group, improved renal function, reduced tubular injury, decreased levels of oxidative stress and apoptosis were observed in CIN rats receiving Sulodexide injection. In addition, we also found that ATIII activity was significantly higher in Sulodexide-administered group than that in vehicle-injected CIN rats. For in vitro studies, HK2 cells were exposed to Ioversol and the cyto-protective effects of Sulodexide were also determined. Sulodexide pretreatment protected HK2 cells against the cytotoxicity of Ioversol via inhibiting caspase-3 activity. Preincubation with Sulodexide could also attenuate H2O2-induced increases in ROS, apoptosis and caspase-3 levels. Conclusions: Taken together, Sulodexide could protect against CIN through activating ATIII, and inhibiting oxidative stress, inflammation and apoptosis.

Sulodexide pretreatment attenuates renal ischemia-reperfusion injury in rats

Sulodexide is a potent antithrombin agent, however, whether it has beneficial effects on renal ischemia-reperfusion injury (IRI) remains unknown. In the present study, we assessed the therapeutic effects of sulodexide in renal IRI and tried to investigate the potential mechanism. One dose of sulodexide was injected intravenously in Sprague-Dawley rats 30 min before bilateral kidney ischemia for 45 min. The animals were sacrificed at 3h and 24h respectively. Our results showed that sulodexide pretreatment improved renal dysfunction and alleviated tubular pathological injury at 24h after reperfusion, which was accompanied with inhibition of oxidative stress, inflammation and cell apoptosis. Moreover, we noticed that antithrombin III (ATIII) was activated at 3h after reperfusion, which preceded the alleviation of renal injury. For in vitro study, hypoxia/reoxygenation (H/R) injury model for HK2 cells was carried out and apoptosis and reactive oxygen species (ROS) levels were evaluated after sulodexide pretreatment. Consistently, sulodexide pretreatment could reduce apoptosis and ROS level in HK2 cells under H/R injury. Taken together, sulodexide pretreatment might attenuate renal IRI through inhibition of inflammation, oxidative stress and apoptosis, and activation of ATIII.

IL-6 receptor blockade ameliorates diabetic nephropathy via inhibiting inflammasome in mice

BACKGROUND AND OBJECTIVE Interleukin 6 (IL-6) has been identified as a key mediator in inflammation, immune responses and glucose metabolism. In this study, we assessed the effects of an IL-6 receptor antibody on diabetic nephropathy in a mouse model of type 2 diabetes mellitus. METHODS Twelve week old male db/db mice were treated with Tocilizumab (an IL-6 receptor antibody), normal IgG1 control antibody, insulin or normal saline for 12 weeks. Renal injury, inflammation and insulin resistance were assessed. RESULTS Db/db mice treated with Tocilizumab exhibited reduced proteinuria and glomerular mesangial matrix accumulation compared to db/db + IgG controls. Additionally, Tocilizumab suppressed inflammatory response, oxidative stress and the IL-6 signaling pathway in the diabetic kidneys. It is noteworthy that blockade of IL-6 receptor blunted the activation of NLRP3 inflammasome partly through inhibition of IL-17A. Furthermore, insulin resistance assessed by glucose tolerance test, was ameliorated by Tocilizumab treatment. CONCLUSIONS The protective effects of an IL-6 receptor blockade against diabetic renal injury may be due to decreased insulin resistance and inhibition of the inflammasome.

Antithrombin III Protects Against Contrast-Induced Nephropathy

We previously reported that insufficiency of antithrombin III (ATIII), the major anti-coagulation molecule in vivo, exacerbated renal ischemia-reperfusion injury in animal models and possibly humans. In the present study, we investigated the relationship between ATIII level and contrast induced nephropathy (CIN) in patients and examined therapeutic effect of ATIII on CIN in Sprague-Dawley rats. Patients with low ATIII activity presented a higher incidence of acute kidney injury (AKI) following coronary angiography. ATIII (500 μg/kg) was intravenously injected before or after the induction of AKI in rats. Our data demonstrated ATIII significantly attenuated the elevation of serum creatinine, blood urea nitrogen, and renal histological injury. The beneficial effects of ATIII were accompanied by diminished renal inflammatory response, oxidative stress, cell apoptosis and improved renal blood flow in rats. In conclusion, ATIII appears to attenuate CIN through inhibiting inflammation, oxidative stress, apoptosis and improving renal blood flow. ATIII administration may represent a promising strategy for the prevention and treatment of contrast-induced AKI.

Underestimated incidence of kidney disease in nonrenal outpatient

Abstract Background and aims: Chronic kidney disease (CKD) has been regarded as a severe threaten to public health, a large percentage of CKD are secondary to other diseases. Serum creatinine is the most common marker of renal function, but it did not always reflect glomerular filtration rate (GFR) accurately. In order to investigate the prevalence of kidney disease in non-renal departments and to provide a basis for the prevention of kidney injury, the present study was conducted in several medical centers. Methods: A total of 17,462 outpatients were selected randomly from the departments of cardiology, endocrinology, and neurology in 16 hospitals and the incidence of kidney disease was screened. Estimated GFR (eGFR) was calculated by using MDRD-formula. Results: There are 5293 (30.1%) patients’ eGFR above 90 mL/min/1.73m2 among all the subjects in non-renal departments, and 4055(23%) patients’ eGFR lower than 60 mL/min/1.73 m2 including 80 patients whose eGFR were below 15 mL/min/1.73 m2. Furthermore, among 16616 subjects who have a normal SCr level, there are 3209 respondents’ eGFR lower than 60 mL/min/1.73 m2. Moreover, individuals with hypertension or diabetes had a high prevalence of decreased renal function. Conclusions: This survey indicated kidney injury wildly existed in non-renal outpatients, and the incidence of CKD is underestimated.

Antithrombin III prevents progression of chronic kidney disease following experimental ischaemic‐reperfusion injury

Acute kidney disease (AKI) leads to increased risk of progression to chronic kidney disease (CKD). Antithrombin III (ATIII) is a potent anticoagulant with anti‐inflammatory properties, and we previously reported that insufficiencies of ATIII exacerbated renal ischaemia‐reperfusion injury (IRI) in rats. In this study, we examined the characteristic of AKI‐CKD transition in rats with two distinct AKI models. Based on our observation, left IRI plus right nephrectomy (NX‐IRI) was used to determine whether ATIII had therapeutic effects in preventing CKD progression after AKI. It was observed that NX‐IRI resulted in significant functional and histological damage at 5 weeks after NX‐IRI compared with sham rats, which was mitigated by ATIII administration. Besides, we noticed that ATIII administration significantly reduced NX‐IRI‐induced interstitial fibrosis. Consistently, renal expression of collagen‐1, α‐smooth muscle actin and fibronectin were substantial diminished in ATIII‐administered rats compared with un‐treated NX‐IRI rats. Furthermore, the beneficial effects of ATIII were accompanied with decreased M1‐like macrophage recruitment and down‐regulation of M1‐like macrophage‐dependent pro‐inflammatory cytokines such as tumour necrosis factor α, inducible nitric oxide synthase and interleukin‐1β, indicating that ATIII prevented AKI‐CKD transition via inhibiting inflammation. Overall, ATIII shows potential as a therapeutic strategy for the prevention of CKD progression after AKI.

Coexistence of Acute Crescent Glomerulonephritis and IgG4-Related Kidney Disease

Introduction: IgG4-related disease (IgG4-RD) is a fibroinflammatory disorder that may involve almost each organ or system. IgG4-related kidney disease (IgG4-RKD) refers to renal lesions associated with IgG4-RD. The most frequent morphological type of renal lesions is IgG4-related tubulointerstitial nephritis (IgG4-TIN) which is associated with increased IgG4-positive plasma cell infiltration and interstitial fibrosis. Case Report: Herein, we present a rare case with coexisting IgG4-RKD and acute crescent glomerulonephritis with concomitant severe tubulointerstitial lesions instead of classic IgG4-TIN. Conclusion: IgG4-RKD and acute crescent glomerulonephritis can occur in the same patient. This case may give us a clearer viewpoint of the disease.

Antithrombin III is a Novel Predictor for Contrast Induced Nephropathy After Coronary Angiography

Background/Aims: Antithrombin Ⅲ (AT Ⅲ) is an important endogenous anticoagulant and has strong anti-inflammatory properties. Low ATⅢ activity is considered to be a predictor of poor outcomes in several conditions, including acute kidney injury after cardiac surgery. However, the association between the ATⅢ level and the occurrence of contrast induced nephropathy (CIN) has not been elucidated. In this study, our aim was to identify the potential predictive value of ATⅢ for CIN. Methods: We enrolled a total of 460 patients who underwent coronary angiography (CAG) from January 2015 to December 2016 in coronary care units (CCU). ATⅢ activity in plasma collected before CAG was measured and <75% was considered low activity according to reference values. A cross-sectional study on CIN after CAG was conducted and the risk factors were analyzed. CIN was diagnosed according to the KDIGO guideline. Results: Of these 460 patients undergoing CAG, 125 (27.17%) progressed to CIN. The incidence of CIN was significantly higher in patients with low ATⅢ activity compared to patients with normal ATⅢ activity (Pearson’s chi-squared test P=0.002). As ATⅢ activity declined, the prevalence of CIN progressively increased, with the highest value (58.8%) in patients with an ATⅢ activity <60%. Moreover, the ATⅢ activity was significantly lower in CIN patients than in non-CIN patients (84.43±16.3% vs. 92.14±13.94%, P<0.001). After multivariable analysis, ATⅢ activity <75% remained a significant independent predictor of CIN (OR 2.207,95%CI [1.29-3.777]; P=0.004) as well as baseline serum creatinine (OR 1.009,95%CI [1.001-1.016]; P=0.026). Conclusions: Patients with low ATⅢ activity had a higher risk of developing CIN after CAG. The initial ATⅢ activity may be a novel independent predictor for CIN.