Activation of GPR120 in podocytes ameliorates kidney fibrosis and inflammation in diabetic nephropathy.

Diabetic nephropathy (DN) is one of the most common causes of end-stage renal disease worldwide. ω3-Fatty acids (ω3FAs) were found to attenuate kidney inflammation, glomerulosclerosis, and albuminuria in experimental and clinical studies of DN. As G protein-coupled receptor 120 (GPR120) was firstly identified as the receptor of ω3FAs, we here investigated the function of GPR120 in DN. We first examined the renal biopsies of DN patients, and found that GPR120 expression was negatively correlated with the progression of DN. Immunofluorescence staining analysis revealed that GPR120 protein was mainly located in the podocytes of the glomerulus. A potent and selective GPR120 agonist TUG-891 (35 mg · kg-1 · d-1, ig) was administered to db/db mice for 4 weeks. We showed that TUG-891 administration significantly improved urinary albumin excretion, protected against podocyte injury, and reduced collagen deposition in the glomerulus. In db/db mice, TUG-891 administration significantly inhibited the mRNA and protein expression of fibronectin, collagen IV, α-SMA, TGF-ß1, and IL-6, and downregulated the phosphorylation of Smad3 and STAT3 to alleviate glomerulosclerosis. Similar results were observed in high-glucose-treated MPC5 podocytes in the presence of TUG-891 (10 µM). Furthermore, we showed that TUG-891 effectively upregulated GPR120 expression, and suppressed TAK1-binding protein-1 expression as well as the phosphorylation of TAK1, IKKß, NF-κB p65, JNK, and p38 MAPK in db/db mice and high-glucose-treated MPC5 podocytes. Knockdown of GPR120 in MPC5 podocytes caused the opposite effects of TUG-891. In summary, our results highlight that activation of GPR120 in podocytes ameliorates renal inflammation and fibrosis to protect against DN.

Development and validation of a model to predict acute kidney injury following wasp stings: A multicentre study.

OBJECTIVE: To establish and validate a model to predict acute kidney injury (AKI) following wasp stings. METHODS: In this multicentre prospective study, 508 patients with wasp stings from July 2015 to December 2019 were randomly divided into a training set (n = 381) and a validation set (n = 127) for internal and external validation. Risk factors were identified, and a model was established to predict the probability of AKI following multiple wasp stings using an individual nomogram and a predictive formula. The performances of the model were assessed by using the area under the curve (AUC), accuracy (ACC) of the receiver operating characteristic curve and decision curve analysis. RESULTS: The number of stings, aspartate aminotransferase >147 U/L, lactate dehydrogenase >477 U/L, time from stings to admission >12 h and activated partial thromboplastin time >49 s were demonstrated to be independent risk factors for AKI following wasp stings (all P value < 0.05) and were incorporated into the model. The performances of the model were validated (AUC = 0.950 [95% CI: 0.923 to 0.969], ACC = 0.916 and AUC = 0.953 [95% CI: 0.900 to 0.982], ACC = 0.906 in the training set and validation set, respectively). The predictive formula and the nomogram of the model could be utilized to predict AKI following wasp stings, which have sufficient accuracies, good predictive capabilities and good net benefits. CONCLUSION: The predictive formula and the individual nomogram of the model might serve as promising predictive tools to assess the probability of AKI following wasp stings.

Pharmacological Inhibition of Macrophage Toll-like Receptor 4/Nuclear Factor-kappa B Alleviates Rhabdomyolysis-induced Acute Kidney Injury.

BACKGROUND:: Acute kidney injury (AKI) is the most common and life-threatening systemic complication of rhabdomyolysis. Inflammation plays an important role in the development of rhabdomyolysis-induced AKI. This study aimed to investigate the kidney model of AKI caused by rhabdomyolysis to verify the role of macrophage Toll-like receptor 4/nuclear factor-kappa B (TLR4/NF-κB) signaling pathway. METHODS:: C57BL/6 mice were injected with a 50% glycerin solution at bilateral back limbs to induce rhabdomyolysis, and CLI-095 or pyrrolidine dithiocarbamate (PDTC) was intraperitoneally injected at 0.5 h before molding. Serum creatinine levels, creatine kinase, the expression of tumor necrosis factor (TNF)-α, interleukin (IL)-1ß and IL-6, and hematoxylin and eosin stainings of kidney tissues were tested. The infiltration of macrophage, mRNA levels, and protein expression of TLR4 and NF-κB were investigated by immunofluorescence double-staining techniques, reverse transcriptase-quantitative polymerase chain reaction, and Western blotting, respectively. In vitro, macrophage RAW264.7 was stimulated by ferrous myoglobin; the cytokines, TLR4 and NF-κB expressions were also detected. RESULTS:: In an in vivo study, using CLI-095 or PDTC to block TLR4/NF-κB, functional and histologic results showed that the inhibition of TLR4 or NF-κB alleviated glycerol-induced renal damages (P < 0.01). CLI-095 or PDTC administration suppressed proinflammatory cytokine (TNF-α, IL-6, and IL-1ß) production and macrophage infiltration into the kidney (P < 0.01). Moreover, in an in vitro study, CLI-095 or PDTC suppressed myoglobin-induced expression of TLR4, NF-κB, and proinflammatory cytokine levels in macrophage RAW264.7 cells (P < 0.01). CONCLUSION:: The pharmacological inhibition of TLR4/NF-κB exhibited protective effects on rhabdomyolysis-induced AKI by the regulation of proinflammatory cytokine production and macrophage infiltration.

Effects of Cyclosporine A on the Development of Metanephros in the Pregnant BALB/c Mice.

BACKGROUND:: Cyclosporine A (CsA) is a commonly used clinical immunosuppressant. However, CsA exposure in rabbits during the gestation period was shown to cause a postnatal decrease in the number of nephrons, with the effects remaining unknown. In this study, we aimed to explore the effects of CsA on metanephros development in the pregnant BALB/c mice. METHODS:: Pregnant mice were randomly divided into two groups, and CsA (10 mg·kg-1·d-1) was subcutaneously injected from gestation day 10.5 to day 16.5 in the CsA group, whereas a comparable volume of normal saline was given to the control group. All of the mice were sacrificed on gestation day 17.5 and serum CsA concentration was measured. The fetuses were removed and weighed, and their kidneys were prepared for histological assessment and polymerase chain reaction assay. In an in vitro experiment, embryo kidneys of fetal mice on gestation day 12.5 were used, and CsA (10 µmol/L) was added in the culture of the CsA group. The growth pattern of the ureteric bud and nephrons was assessed by lectin staining. RESULTS:: No significant differences in the weight of embryo (4.54 ± 1.22 vs. 3.26 ± 1.09 mg) were observed between the CsA and control groups, the thickness of the cortical (510.0 ± 30.3 vs. 350.0 ± 29.7 µm, P < 0.05) and nephrogenic zone (272.5 ± 17.2 vs. 173.3 ± 24.0 µm, P < 0.05), and the number of glomeruli (36.5 ± 0.7 vs. 27.5 ± 2.1, P < 0.05) were reduced in the CsA group when compared to the control group. The cell proliferation of Ki-67 positive index between control and CsA group (307.0 ± 20.0 vs. 219.0 ± 25.0, P < 0.05) in the nephrogenic zone was decreased with the increase of apoptotic cells (17.0 ± 2.0 vs. 159.0 ± 33.0, P < 0.05). The mRNA expression of WT-1, Pax2, and Pax8 was downregulated by CsA treatment. As for the in vitro CsA group, the branch number of the ureteric bud was decreased in the CsA-treated group with the nephrons missing in contrast to control after the incubation for 24 h and 72 h (all P < 0.0001). CONCLUSION:: Treatment of CsA suppressed metanephros development in the pregnant mice; however, the potential action of mechanism needs to be further investigated.

Renoprotective Effect of the Combination of Renin-angiotensin System Inhibitor and Calcium Channel Blocker in Patients with Hypertension and Chronic Kidney Disease.

BACKGROUND: Renin-angiotensin system inhibitor and calcium channel blocker (CCB) are widely used in controlling blood pressure (BP) in patients with chronic kidney disease (CKD). We carried out a meta-analysis to compare the renoprotective effect of the combination of angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) and CCB (i.e., ACEI/ARB + CCB) with ACEI/ARB monotherapy in patients with hypertension and CKD. METHODS: Publications were identified from PubMed, Embase, Medline, and Cochrane databases. Only randomized controlled trials (RCTs) of BP lowering treatment for patients with hypertension and CKD were considered. The outcomes of end-stage renal disease (ESRD), cardiovascular events, BP, urinary protein measures, estimated glomerular filtration rate (GFR), and adverse events were extracted. RESULTS: Based on seven RCTs with 628 patients, ACEI/ARB + CCB did not show additional benefit for the incidence of ESRD (risk ratio [RR] = 0.84; 95% confidence interval [CI]: 0.52-1.33) and cardiovascular events (RR = 0.58; 95% CI: 0.21-1.63) significantly, compared with ACEI/ARB monotherapy. There were no significant differences in change from baseline to the end points in diastolic BP (weighted mean difference [WMD] = -1.28 mmHg; 95% CI: -3.18 to -0.62), proteinuria (standard mean difference = -0.55; 95% CI: -1.41 to -0.30), GFR (WMD = -0.32 ml/min; 95% CI: -1.53 to -0.89), and occurrence of adverse events (RR = 1.05; 95% CI: 0.72-1.53). However, ACEI/ARB + CCB showed a greater reduction in systolic BP (WMD = -4.46 mmHg; 95% CI: -6.95 to -1.97), compared with ACEI/ARB monotherapy. CONCLUSION: ACEI/ARB + CCB had no additional renoprotective benefit beyond than what could be achieved with ACEI/ARB monotherapy.