Induced Kidney Injury Research Articles

Prescription Drug Overdose, Depression, and Other Mental Disorders in the Context of Kidney Disease.

Clinical Background: Mental disorders, especially depression, are associated with several comorbidities in the kidneys. Depression is the psychiatric disorder that mostly affects individuals with chronic kidney disease (CKD) and end-stage kidney disease. Epidemiology: The mainly prescribed drugs involved in overdose cases are opioids, benzodiazepines, and antidepressants. Antidepressants are the main psychiatric drugs that lead to kidney injury, mainly the second-generation ones. However, the prevalence of depression in dialysis patients varies from 22.8 to 39.3%. Therefore, psychiatric patients have 1.5-3 times more hospitalization compared to patients having only CKD. Challenges: Randomized clinical studies should be encouraged. Studies have shown an association between depression and progression of kidney disease. The mechanisms are not completely clear, but changes on neurotransmitter release and endocrine functions appear to be related to it. Additionally, the use of antidepressant and other psychoactive drugs can induce kidney injury. Hyponatremia induced by second-generation antidepressant drugs is an important feature and can be a risk factor for elderly or patients with comorbidities such as cerebral edema, brain damage or coma. Besides this class, drugs used for anxiety and bipolar disorders or sympathomimetic drugs of abuse can trigger acute kidney injury, possibly due to endothelial dysfunction and thromboembolic and ischemic events. Prevention and Treatment: The early detection of renal impairment and the prescription of nephroprotective strategies has been a clinical challenge. Some studies aim to describe the biochemical mechanisms involved and develop clinical management strategies for these patients. This chapter brings attention to this topic, discussing the major mechanisms and clinical features of kidney injury associated with mental illness, and the most relevant clinical strategies.

Drug-resistant Salmonella Typhi induced kidney injury with rhabdomyolysis: A case report, and literature review

Salmonella Typhi (ST) is a rod-shaped gram-negative bacterium that infects humans via contaminated food or water. Humans are the only reservoirs for the bacteria. Infection usually manifests as fever, abdominal pain, and diarrhea. However, complications such as intestinal perforation, hepatosplenomegaly, and renal injury can occasionally occur. Acute kidney injury (AKI) is associated more commonly with ST than other bacteria causing gastrointestinal (GI) infections. The exact pathophysiology of AKI in ST infection is unknown. One of the rarely reported mechanisms is rhabdomyolysis. We present a similar case of resistant ST infection leading to AKI with rhabdomyolysis. This article also contains an extensive literature reviews of all reported ST bacteremia cases with AKI secondary to rhabdomyolysis.

Bovine serum albumin aggravates macrophage M1 activation and kidney injury in heterozygous Klotho-deficient mice via the gut microbiota-immune axis.

Klotho expression abnormalities induces kidney injury and chronic kidney disease, however, the underlying mechanism remains unclear. Here, Klotho+/- mice and wild-type mice were treated with low-dose bovine serum albumin (BSA). Pathological examination demonstrated that the area of glomerular collagen deposition and fibrosis in BSA-Kl-/+ mice was significantly larger than that in BSA-WT mice. The serum levels of superoxide dismutase, malondialdehyde, creatinine, and urea in BSA-Kl-/+ mice were significantly increased. Sequencing of gut microbiota 16S rRNA v3-v4 region indicated that BSA-Kl-/+ mice showed a significantly higher relative abundance of the genera Dubosiella, Akkermansia, Alloprevotella, and Lachnospiraceae and a significantly lower relative abundance of the genera Allobaculum and Muribaculaceae than BSA-WT mice. KEGG analysis revealed that the metabolic pathways of signal transduction, xenobiotic biodegradation and metabolism, and lipid metabolism increased significantly in BSA-Kl-/+ mice. Flow cytometry showed that the proportion of CD68+/CD11b+ cells in the peripheral blood was significantly higher in BSA-KL-/+ mice than that in BSA-WT mice. qPCR and western blot suggested that Klotho and Nrf2 expression in MΦ1 cells of BSA-KL-/+ mice was significantly decreased. Thus, the findings suggest during the immune activation and chronic inflammation induced by the gut microbiota imbalance in Klotho-deficient mice treated to BSA, disrupted expression of proteins in the Nrf2/NF-κB signaling pathway in monocyte-derived macrophage M1 cells leads to the aggravation of inflammation and kidney injury.

Withaferin A protects against hyperuricemia induced kidney injury and its possible mechanisms

ABSTRACT The study was designed to explore the effects of Withaferin A (WFA) on hyperuricemia-induced kidney injury and its action mechanism. Potassium oxonate (PO) was employed to establish the hyperuricemic mouse model. The pathological changes of renal tissue were evaluated by hematoxylin-eosin and masson trichrome staining. The levels of creatinine, blood urea nitrogen (BUN), uric acid (UA) and xanthine oxidase (XOD) were detected using corresponding commercial kits. Expressions of collagen-related and apoptosis-associated proteins in renal tissues were, respectively, evaluated by immunofluorescence and western blotting. Cell apoptosis was detected by TUNEL assay, and transporter expressions using western blotting. Followed by WFA, NRK-52E cells were treated with UA before evaluation of apoptosis and fibrosis. Results indicated that WFA ameliorated renal damage, improved kidney function, and decreased levels of creatinine, BUN, UA, and XOD in PO-induced hyperuricemic mice. Furthermore, WFA significantly prevented renal fibrosis and increased the expression of collagen-related proteins. Similarly, WFA markedly inhibited renal apoptosis, accompanied by changes of apoptosis-related proteins. Importantly, expression of transporters responsible for the secretion of organic anion transporter 1 (OAT1), OAT3, ATP-binding cassette subfamily G member 2 (ABCG2) was remarkably enhanced whereas that of urate transporter 1 (URAT1) and glucose transporter 9 (GLUT9) was reduced in renal tissues of mice with hyperuricemia. In vitro study revealed that WFA notably ameliorated UA-induced cell fibrosis and apoptosis. Taken together, WFA improves kidney function by decreasing UA via regulation of XOD and transporter genes in renal tubular cells.

Clinical Characteristics and Outcomes of Patients With Severe COVID-19 Induced Acute Kidney Injury

The incidence and outcome of Coronavirus disease 2019 (COVID-19)-induced kidney injury have been variably described. We aimed to describe the clinical characteristics, correlates and outcomes of critically ill patients with severe COVID-19 complicated by acute kidney injury (AKI). We performed a multicenter retrospective cohort study of 671 critically ill adults with laboratory-confirmed COVID-19 from 19 hospitals in China between January 1 to February 29, 2020. Data were captured on demographics, comorbidities, symptoms, acute physiology, laboratory parameters, interventions, and outcomes. The primary exposure was ICU admission for confirmed COVID-19 related critically illness. The primary outcome was 28-day mortality. Secondary outcomes included factors associated with AKI, organ dysfunction, treatment intensity, and health services use. Of 671 severe COVID-19 patients (median [IQR] 65 [56-73] years; male sex 65% (n = 434); hypertension 43% (n = 287) and APACHE II score 10 [7-14]), 39% developed AKI. Patients with AKI were older, had greater markers of inflammation and coagulation activation, and had greater acuity and organ dysfunction as presentation. Despite similar treatment with antivirals, patients with AKI had lower viral conversion negative rates than those without AKI. The 28-day mortality was much higher in AKI patients than patients without AKI (72% vs. 42%), and there was an increase in 28-day mortality according to the severity of AKI. Non-survivors were less likely to receive antiviral therapy [132 (70%) vs. 65 (88%)] compared with survivors and have lower viral negative conversion rate [17 (9%) vs. 47 (64%)]. Acute kidney injury was quite common in severe COVID-19 pneumonia, which associated with higher mortality.

Abstract 14808: Acute Kidney Injury and Adverse Outcomes in Patients Undergoing Right Heart Catheterization versus Patients Undergoing Right and Left Heart Catheterization and Coronary Angiography

Background: Contrast induced nephropathy (CIN), or contrast-induced acute kidney injury is considered a complication of intravascular administration of iodinated contrast material. However, more recent studies have challenged the reported incidence of contrast nephropathy. We compared the incidence of acute kidney injury and of nephropathy at 3 months in patients undergoing only right heart catheterization (RHC) to patients undergoing right and left heart catheterization (R&LHC) and coronary angiography. Methods and Results: We studied 1779 consecutive patients at a Veterans Administration Medical Center, of which 869 underwent only RHC, which does not involve the administration of iodinated contrast media, and 910 patients who underwent R&LHC and coronary angiography. Creatinine values at 72 hours after the respective procedure were available in 938 patients and creatinine values at 3 months were available in 1246 patients. The incidence of acute kidney injury (defined as an increase in serum creatinine of 0.5 mg/dL or 25% compared to baseline) at 3 days was 34 (7.5%) in the RHC group and 46 (9.5%) in the R&LHC group (P=0.31). The incidence of nephropathy at 3 months was 89 (15.6%) in the RHC group and 113 (12.2%) in the R&LHC group (P=0.15). On multivariable analysis including adjustment for a propensity score, CIN at 3 days was not significantly associated with R&LHC (odds ratio (OR) 1.02, 95% confidence interval (CI) 0.98-1.05; P=0.56) and neither was nephropathy at 3 months (OR 1.01, 95% CI 0.98-1.04; P=0.22). Patients undergoing R&LHC had a lower mortality at 12 months (hazard ratio 0.57, 95% CI 0.43-0.77; P<0.001). Conclusions: The incidence of acute kidney injury was not significantly different in patients undergoing RHC compared to patients undergoing R&LHC and coronary angiography, even though the former received no contrast dye. The incidence of nephropathy at 3 months was also not significantly different between the two groups while mortality was significantly lower in the group of patients undergoing R&LHC. This suggests that serum creatinine is a nonspecific diagnostic marker for contrast induced-kidney injury and that long-term outcomes are not associated with the administration of contrast in this population.

Nephrotoxicity and possible mechanisms of decabrominated diphenyl ethers (BDE-209) exposure to kidney in broilers

The flame retardant decabrominated diphenyl ether (BDE-209) is a widely used chemical in a variety of products and exists extensively in the environment. BDE-209 has been reported to induce kidney injury and dysfunction. However, the causes and mechanisms of its nephrotoxicity are still under investigation. In this study, 150 male broilers were exposed to BDE-209 concentrations of 0, 0.004, 0.04, 0.4, 4.0 g/kg for 42 days. The relative kidney weight, histopathology, markers of renal injury, oxidative stress, inflammation, apoptosis and the expression of MAPK signaling pathways-related proteins were assessed. The results showed that the concentrations of blood urea nitrogen (BUN), creatinine (CRE) and the neutrophil gelatinase-associated lipocalin (NGAL), significantly increased after exposure to BDE-209 with the doses more than 0.04 g/kg. Similarly, severe damage of renal morphology was observed, including atrophy and necrosis of glomeruli, and swelling and granular degeneration of the renal tubular epithelium. In the renal homogenates, the oxidative stress was evidenced by the elevated concentrations of MDA and NO, and decreased levels of GSH-Px, GSH and SOD. Due to the inflammatory response, the level of NF-κB and the pro-inflammatory cytokines TNF-α, IL-1β, IL-18 were remarkably upregulated, while the content of the anti-inflammatory cytokine IL-10 decreased. Additionally, the apoptotic analysis showed notable upregulations of Bax/Bcl-2 ratio, the relative expression of p-ERK1/2 and p-JNK1/2, and the expression of Bax, cytochrome c and caspase 3. The present study indicates that BDE-209 exposure can cause nephrotoxicity in broilers through oxidative stress and inflammation, which activate the phosphorylation of key proteins of the MAPK signaling pathways, and subsequently induce mitochondria-mediated kidney apoptosis.

Modular Microphysiological System for Modeling of Biologic Barrier Function.

Microphysiological systems, also known as organs-on-chips, are microfluidic devices designed to model human physiology in vitro. Polydimethylsiloxane (PDMS) is the most widely used material for organs-on-chips due to established microfabrication methods, and properties that make it suitable for biological applications such as low cytotoxicity, optical transparency, gas permeability. However, absorption of small molecules and leaching of uncrosslinked oligomers might hinder the adoption of PDMS-based organs-on-chips for drug discovery assays. Here, we have engineered a modular, PDMS-free microphysiological system that is capable of recapitulating biologic barrier functions commonly demonstrated in PDMS-based devices. Our microphysiological system is comprised of a microfluidic chip to house cell cultures and pneumatic microfluidic pumps to drive flow with programmable pressure and shear stress. The modular architecture and programmable pumps enabled us to model multiple in vivo microenvironments. First, we demonstrate the ability to generate cyclic strain on the culture membrane and establish a model of the alveolar air-liquid interface. Next, we utilized three-dimensional finite element analysis modeling to characterize the fluid dynamics within the device and develop a model of the pressure-driven filtration that occurs at the glomerular filtration barrier. Finally, we demonstrate that our model can be used to recapitulate sphingolipid induced kidney injury. Together, our results demonstrate that a multifunctional and modular microphysiological system can be deployed without the use of PDMS. Further, the bio-inert plastic used in our microfluidic device is amenable to various established, high-throughput manufacturing techniques, such as injection molding. As a result, the development plastic organs-on-chips provides an avenue to meet the increasing demand for organ-on-chip technology.

Novel Evidence of Acute Kidney Injury in COVID-19.

The coronavirus 2019 (COVID-19) pandemic has caused a huge impact on health and economic issues. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes cellular damage by entry mediated by the angiotensin-converting enzyme 2 of the host cells and its conjugation with spike proteins of SARS-CoV-2. Beyond airway infection and acute respiratory distress syndrome, acute kidney injury is common in SARS-CoV-2-associated infection, and acute kidney injury (AKI) is predictive to multiorgan dysfunction in SARS-CoV-2 infection. Beyond the cytokine storm and hemodynamic instability, SARS-CoV-2 might directly induce kidney injury and cause histopathologic characteristics, including acute tubular necrosis, podocytopathy and microangiopathy. The expression of apparatus mediating SARS-CoV-2 entry, including angiotensin-converting enzyme 2, transmembrane protease serine 2 (TMPRSS2) and a disintegrin and metalloprotease 17 (ADAM17), within the renal tubular cells is highly associated with acute kidney injury mediated by SARS-CoV-2. Both entry from the luminal and basolateral sides of the renal tubular cells are the possible routes for COVID-19, and the microthrombi associated with severe sepsis and the dysregulated renin–angiotensin–aldosterone system worsen further renal injury in SARS-CoV-2-associated AKI. In the podocytes of the glomerulus, injured podocyte expressed CD147, which mediated the entry of SARS-CoV-2 and worsen further foot process effacement, which would worsen proteinuria, and the chronic hazard induced by SARS-CoV-2-mediated kidney injury is still unknown. Therefore, the aim of the review is to summarize current evidence on SARS-CoV-2-associated AKI and the possible pathogenesis directly by SARS-CoV-2.

Current insights toward kidney injury: Decrypting the dual role and mechanism involved of herbal drugs in inducing kidney injury and its treatment

• The kidney performs a significant role in the excretion of xenobiotics. • Alteration to physiological processes leads to kidney injury leading to the precipitation of kidney diseases. • Kidney injury is precipitated by the long-term use of nephrotoxic materials, either synthetic or herbal medicines used to treat various chronic diseases. • Efficient analytical techniques and high end modern advanced techniques specific to herbal medicines are required to improvise their usage in the market for all needs. The kidney is essential for the physiological functions of the body. When exposed to high concentrations of toxins, these may induce the toxicity of the kidney (kidney injury), leading to renal failure and precipitating a condition called nephrotoxicity. The toxicity may result from hemodynamic changes and directly harm the cells and tissue, and causes obstruction of renal excretion. Nephrotoxicity can also be induced by renal impairment leads to kidney-specific detoxification and diminished kidney function by ischemia and toxicants/drugs. Considering the possible damage to kidneys by drugs, patients are using the naturally derived substance, including herbal drugs or nutraceuticals. However, the safety concerns of herbal drugs and formulation in inducing kidney injury are an area of research. The present review is a concerted effort to assemble information mainly focusing on the kidney injury, its comprehensive categorization, i.e., mechanism of interaction of various enzyme systems of kidneys with drugs of herbal and synthetic origin and their outcomes. Moreover, the review also put forth the details of herbal drug that precipitate kidney injury and ameliorate it. The review is being put forward with an incentive to provide researchers with a comprehensive and updated literature on kidney injury by drugs of natural and synthetic origin and their molecular targets in the kidney.

A Murine Model Of Kidney Injury: The role of SMPDL3b In Radiation And Cisplatin-Induced Nephrotoxicity

Cisplatin is widely used as a chemotherapeutic agent and a known radiosensitizer. The current study aimed to investigate the role of lipid-modulating enzyme sphingomyelin phosphodiesterase acid-like 3B (SMPDL3b) in cisplatin toxicity. Nephrotoxicity is dose-limiting toxicity. Cultured oocytes were treated with rituximab mAb (100 μg/ml) or IgG (100 μg/ml) 30 minutes before irradiation with 0-8 Gy, with or without Cisplatin (2μM). In other experiments, 10–14-week old C57BL/6 male and female mice were given bilateral kidney X-irradiation (4Gyx1, 6 Gyx5, and 2Gyx24) with or without Cisplatin (6mg/kg, IP). Animals received rituximab mAb (RTX) or IgG (50mg/kg; IV) 30 minutes before radiation treatment. Functional kidney parameters (serum BUN, hematocrit, and creatinine), histopathological assessments (oil red staining, H&E, Periodic Acid-Schiff, and TEM) and biochemical changes were studied at baseline, 10- and 20-weeks post-chemo-radiotherapy. Glomerular filtration rate (GFR) was estimated at 10- and 20-weeks post-radiation using FITC-sinistrin based transdermal monitor and iSMAART dynamic contrast-enhanced (DCE) imaging. RT and concurrent Cisplatin (2 μM) produced time-dependent apoptosis in wild-type human podocytes, causing an 85% increase in caspase 3 activity 2h post-RT (8Gy). Different doses of RT, 1x4Gy, 1x10Gy, and 1x14Gy increased glomerular base membrane (GBM) thickness in irradiated mice significantly (100%, 150%, and 200% respectively). Cisplatin and RT (1x4Gy) increased GBM thickness from 225nm to 425nm, respectively (p = 0.01). The eGFR values changed significantly from 1010±214 to 718±205, 687±175, 508±56, 596±180, and 639±221 mL/min after x4Gy, 1x10Gy, 1x14Gy, 5x6Gy, and 24x2Gy, respectively. RTX pretreatment improved eGFR and other functional parameters (serum BUN, hematocrit, serum creatinine, and urine albumin/creatinine ratio (ACR) significantly post chemoradiotherapy. RTX pretreatment protected podocytes cytoskeletal remodeling in vitro and foot process effacement in vivo. SMPDL3b expression and podocytes count significantly decreased post chemoradiotherapy. RTX ameliorated SMPDL3b down-regulation, and improved podocytes count significantly. This study shows that RTX pretreatment protects podocytopathy in vitro and chemoradiation induced kidney injury in vivo. SMPDL3b may be an important therapeutic target for radiation-induced kidney injuries in cancer patients.

Combine colorants of tartrazine and erythrosine induce kidney injury: involvement of TNF-α gene, caspase-9 and KIM-1 gene expression and kidney functions indices

Twenty-five male Wistar rats (140–170 g) were partitioned into 5 groups (n = 5). 2.5 mg/kg, 5 mg/kg, 10 mg/kg and 20 mg/kg of combine Tartrazine and Erythrosine (T+E; 50:50) were administered for 23 days. Serum urea and creatinine, gene expression and profiling of pro-inflammatory cytokine (Tumor Necrosis Factor- α gene), Caspase-9 and Kidney injury molecule-1 (KIM-1) and histomorphological examination of the kidney were investigated. The fold change of relative gene expression of TNF-α gene showed significantly (p < 0.05) up-regulation in all the treated rats except for the 10 mg/kg T+E treated rats when compared to control rats. Casp-9 and KIM-1 genes were significantly (p < 0.05) up-regulated in low dose treatment (2.5 mg/kg T+E and 5 mg/kg T+E) and down-regulated in high dose treatment (10 mg/kg T+E and 20 mg/kg T+E). However, there was significant (p < 0.05) increase in serum urea concentration in the rats treated with 5 mg/kg T+E and 20 mg/kg T+E while the rats treated with 10 mg/kg T+E indicated a significant (p < 0.05) decrease. Conversely, serum creatinine concentration indicated significant (p < 0.05) increase in10mg/kg T+E and 20 mg/kg T+E treated rats versus the control. From the histomorphological examination of the kidney, there was hypertrophy of the glomeruli in relation to the size of Bowman’s capsule in the 10 mg/kg T+E and 20 mg/kg T+E treated rats. Kidney function was impaired as evident in up-regulation of TNF-α gene, KIM-1 gene, and serum urea and creatinine concentration with down-regulation of Casp-9 gene. The combined treatment also tampers with the architecture of the kidney.

Nephroprotective and antioxidant activities of ethyl acetate fraction of Euphorbia geniculata Ortega family Euphorbiaceae

In continuation of our work on genus Euphorbia, the phytochemical investigation of ethyl acetate fraction of the aerial parts of Euphorbia geniculata Ortega (Eg) family Euphorbiaceae revealed the isolation and identification of eight polyphenolic compounds; gallic acid (1), ellagic acid (2), quercetin-3-O-rutinoside) (rutin) (3), quercetin-3-O-glucopyranoside-7-O-rhamnoside (4), quercetin-3-O-rhamnoside (5), quercetin-3-O-β-D- glucopyranoside (6), and quercetin-3-O-β-D-arabinoside (7) and quercetin (8) using spectrophotometric and physicochemical analysis. Quantitative estimation of total flavonoids and phenolics contents were carried out for total methanolic extract. Biological activities of ethyl acetate fraction including nephroprotective and antioxidant activities were evaluated for the first time. The nephroprotective potential of Eg was evaluated in male rats with thioacetamide induced kidney injury. Antioxidant activity was evaluated using DPPH method.Results; Quantitative estimation of total phenolics and flavonoids content in the total methanolic extract of Eg revealed high phenolics content (285.4 mg GAE /gm extract) in comparison with flavonoids content (36.9 mg RE /gm extract). Isolation and characterization of eight polyphenolic compounds. The nephroprotictive activity was studied using thioacetamide as nephrotoxicant agent resulted in marked nephrotoxicity. While pretreatment of rats with ethyl acetate fraction of Eg significantly attenuated the nephrotoxicity through alteration of kidney biomarkers, improving the redox status of the tissue and so brought the serum biochemical parameters nearly toward the normal levels. The study revealed significant antioxidant activity of Eg in comparison with ascorbic acid. Conclusion; The results suggested that E. geniculata Ortega ethyl acetate fraction could be used in future therapy as nephroprotective and antioxidant drugs of natural source.

Some Aspects of Drug Induced Nephrotoxicity Assessment

About 14‒23% of all clinically used drugs have nephrotoxic potential and are a frequent cause of acute and chronic kidney problems. Acute kidney injury (AKI) is associated with a high risk of repeat hospitalisation, complications, and mortality in adults and children. The aim of the study was to provide an overview of the current approaches to the assessment of drug induced nephrotoxicity. The paper summarises pathogenetic mechanisms of drug induced kidney injury as well as molecular mechanisms at the drug transporters level. It analyses risk factors for drug induced kidney injury—age, sex, ethnicity, comorbidities (chronic kidney disease, diabetes, cardiovascular disease, immune disorders, sepsis, etc.), drug dosage and duration of therapy, pharmacokinetics of drugs, combinations of potentially nephrotoxic drugs, genetic determinants of drug metabolism and transport, etc. It was demonstrated that the traditional nephrotoxicity markers—serum creatinine and urine output—have low sensitivity as indicators of early renal damage. Therefore, new kidney biomarkers are being sought for in order to be used in AKI diagnosis and monitoring in patients with different comorbidities. Some of these biomarkers are already used in drug development, preclinical and clinical trials for assessment and prediction of drug safety. The analysis showed that none of these new kidney biomarkers could be used as an all-purpose tool in routine clinical practice. The development of new AKI biomarkers is a long-range objective and is the path toward early diagnosis and successful treatment of drug-induced nephrotoxicity.

Ameliorating Effect of Pentadecapeptide Derived from Cyclina sinensis on Cyclophosphamide-Induced Nephrotoxicity.

Cyclophosphamide (CTX) is a widely used anticancer drug with severe nephrotoxicity. The pentadecapeptide (RVAPEEHPVEGRYLV) from Cyclina sinensis (SCSP) has been shown to affect immunity and to protect the liver. Hence, the purpose of this study was to investigate the ameliorating effect of SCSP on CTX-induced nephrotoxicity in mice. We injected male ICR mice with CTX (80 mg/kg·day) and measured the nephrotoxicity indices, levels of antioxidant enzymes, malondialdehyde (MDA), inflammatory factors, as well as the major proteins of the NF-κB and apoptotic pathways. Cyclophosphamide induced kidney injury; the levels of kidney-injury indicators and cytokines recovered remarkably in mice after receiving SCSP. The activities of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and catalase (CAT) increased, while there was a significant decrease in MDA levels. The kidney tissue damage induced by CTX was also repaired to a certain extent. In addition, SCSP significantly inhibited inflammatory factors and apoptosis by regulating the NF-κB and apoptotic pathways. Our study shows that SCSP has the potential to ameliorate CTX-induced nephrotoxicity and may be used as a therapeutic adjuvant to ameliorate CTX-induced nephrotoxicity.

The phosphodiesterase 5 inhibitor tadalafil has renoprotective effects in a rat model of chronic kidney disease.

Phosphodiesterase 5 inhibitors are widely used to treat erectile dysfunction and lower urinary tract symptoms with benign prostatic hyperplasia. Recent studies have indicated the renoprotective effects of this class of compounds. Whether renoprotection depends on blood pressure reduction remains controversial. In this study, we investigated the renoprotective effects of the phosphodiesterase 5 inhibitor, tadalafil, in a rat model of high‐salt induced kidney injury with hypertension. Dahl salt‐sensitive rats were fed a normal diet, high‐salt (8% sodium chloride) diet, or high‐salt diet with oral administration of either low‐ or high‐dose tadalafil (1 and 10 mg kg−1 day−1, respectively). Serum creatinine, urinary protein, and blood pressure were measured at baseline and after 8 weeks, at which point the rats were examined for glomerular injury and fibrosis. PAI1 mRNA levels were also evaluated. After 8 weeks, blood pressure, serum creatinine, and urinary protein levels were significantly higher in the high‐salt group than those in the normal‐salt group. Serum creatinine and urinary protein were significantly lower in both tadalafil groups than those in the high‐salt group, while only high‐dose tadalafil affected blood pressure. In addition, glomerulosclerosis and α‐smooth muscle actin expression significantly decreased in both tadalafil treatment groups. PAI1 mRNA increased significantly in the high‐salt group but decreased in both tadalafil‐treated groups. Our results indicated that both low‐ and high‐dose tadalafil prevented fibrosis and glomerular injury in a chronic kidney disease rat model. Mechanistically, these effects may be associated with PAI1 expression and glomerular structure protection.

Liraglutide protects against high-fat diet-induced kidney injury by ameliorating apoptosis.

BackgroundObesity is associated with the development and progression of chronic kidney disease. Emerging evidence suggests that glucagon-like peptide-1 receptor agonist could reduce renal damage and albuminuria. Sirtuin 1 (SIRT1) was considered as a crucial regulator in metabolism-related kidney disease. Herein, the role of SIRT1 in liraglutide-ameliorated high-fat diet (HFD)-induced kidney injury was illustrated.MethodsMale C57BL/6 mice were fed HFD for 20 weeks to induce kidney injury that was then treated with liraglutide for 8 weeks to estimate its protective effect on the kidney. Also, the mechanism of the drug in SV40 MES 13 (SV40) mouse mesangial cells was elucidated.ResultsLiraglutide treatment ameliorated HFD-induced metabolic disorders, including hyperglycemia, increasing body weight, and insulin resistance. In addition, kidney weight, urine albumin-to-creatinine, and kidney morphological changes such as vacuolated tubules, glomerulomegaly, thickened glomerular basement membrane, and tubulointerstitial fibrosis were also significantly ameliorated. Furthermore, apoptotic cells and apoptosis markers were downregulated in the kidney of liraglutide-treated mice. In addition, the expression of SIRT1 protein was upregulated, whereas thioredoxin-interacting protein (TXNIP), which serves as a mediator of oxidative stress and apoptosis in metabolism disease, was downregulated by liraglutide. In SV40 cells, the effect of liraglutide on reversing the upregulation of cleaved caspase-3 induced by high glucose (30 mM) was hampered when SIRT1 was knocked down; also, the downregulation of TXNIP by liraglutide was blocked.ConclusionsLiraglutide might have a beneficial effect on metabolism-related kidney damage by inhibiting apoptosis via activation of SIRT1 and suppression of TXNIP pathway.

Abstract P004: Endothelial Function In Rat Juxtamedullary Afferent Arterioles After Renal Ischemia-reperfusion Injury

Renal ischemia-reperfusion (IR) induced kidney injury exhibits reduced renal blood flow (RBF) and glomerular filtration rate (GFR). Both RBF and GFR are regulated by renal microvascular function. Our previous study showed that IR caused impaired afferent arteriole autoregulatory capability via excess ROS accumulation and inflammation in renal microvessels. Other mechanisms contributing to renal microvascular dysfunction in IR have not been fully defined. In this study, we conducted acetylcholine (ACh) concentration-response experiments (n=5-7/each group) to assess endothelial function using the in vitro blood-perfused juxtamedullary nephron preparation. IR was induced by 60 minutes of bilateral renal artery occlusion followed by 24 hours or 7 days of reperfusion. Renal microvessels (RMV) were collected at either 24 hours or 7 days post-surgery for mRNA analysis. Systolic blood pressure was normal in IR rats vs. sham ranging from 126-136 mmHg (&gt;0.05) over 7 days. IR markedly increased plasma creatinine concentration (Cr) to 3.9±0.2 mg/dL at 24 hours post-IR ( P &lt;0.05 vs. 0.9±0.1 mg/dL in sham). Plasma Cr remained elevated in IR rats by day 7 of reperfusion (1.5±0.2 vs. 1.0±0.0 mg/dL in sham, P &lt;0.05). Baseline afferent arteriole diameter was smaller in IR rats 24 hours post-IR and averaged 11.1±0.7 μm (P&lt;0.05 vs. 14.2±0.7 μm in sham). Superfusion of ACh (10 -8 to 10 -4 M) caused concentration-dependent vasodilation in sham rats, increasing diameter to 23.5±2.6 μm (169±14% of the control, P &lt;0.05) at 10 -4 M ACh. The ACh-induced vasodilation was not altered by IR insult and was indistinguishable from the sham responses. IR diameter reached a maximum of 19.7±0.9 μm (179±8% of the control) at 10 -5 M ACh. The ACh responses were also similar between sham and IR rats on day 7 post-IR. mRNA expression of endothelial markers, iCAM and vCAM, were not statistically different in RMV collected at 24 hours post-surgery between two groups, but was markedly elevated in IR RMV on day 7 post-IR (4-fold in iCAM and 2-fold in vCAM, P&lt;0.05 vs. sham). In conclusion, upregulation of iCAM and vCAM mRNA expression in RMV 7 days post-IR suggests renal microvascular inflammation, but rat juxtamedullary afferent arterioles still maintain normal endothelium-dependent reactivity to ACh.

Se deficiency induces renal pathological changes by regulating selenoprotein expression, disrupting redox balance, and activating inflammation.

Selenium (Se) is closely associated with kidney disease, and renal injury often occurs together with hyposelenemia. This study was designed to reveal the mechanism underlying renal injury induced by Se deficiency in pigs. Twenty-four castrated male Yorkshire pigs were divided into two groups fed either a Se-deficient diet (0.007 mg Se per kg) or a Se-adequate diet (0.3 mg Se per kg). Serum and kidney samples were collected at the 16th week of the trial, processed, and analyzed for serum biochemistry, Se concentration, kidney index markers, histology, selenoprotein mRNA expression, redox status, and inflammatory cytokines. Dietary Se deficiency induced kidney injury, decreased (P < 0.05) Se concentrations, and increased (P < 0.05) kidney index and serum blood urea nitrogen, creatinine, and carbon dioxide values. Histological analysis indicated that Se deficiency induced inflammatory lesions and renal tubular atrophy in the renal medulla. Se deficiency downregulated (P < 0.05) nine selenoprotein genes (GPX1, SELENOW, SELENOH, SELENOP, GPX3, TXNRD2, SELENOI, SELENON, and SELENOM) and upregulated (P < 0.05) SEPHS2 in the kidneys. Se deficiency decreased (P < 0.05) the activity of glutathione peroxidase, thioredoxin reductase, and catalase, as well as the hydroxyl radical inhibition capacity, and increased (P < 0.05) the content of malondialdehyde and nitric oxide. Se deficiency increased (P < 0.05) the expression of the transcription factors NF-κB and HIF-1α, and regulated inflammatory cytokines. Se deficiency increased (P < 0.05) the expression of IL-6, IL-8, IL-12, IL-17, and cyclooxygenase-2, and decreased (P < 0.05) the expression of IL-10, IL-13, and TGF-β. These results indicated that Se deficiency induces kidney injury through the regulation of selenoproteins, oxidative stress, and inflammation.

Cellular Senescence: A New Player in Kidney Injury.

Kidney diseases secondary to several pathogeneses affect millions of people worldwide and have become increasingly recognized as a global public health problem. Recent evidence suggests that cellular senescence plays an important role in the pathogenesis of different forms of renal damage, including acute and chronic kidney disease, and renal transplantation. Renal senescence involves cell cycle arrest and affects several cellular pathways, manifesting in downregulation of klotho, elevated expression of cyclin-dependent kinase inhibitors, cellular telomere shortening, and oxidative stress. Furthermore, senescent cells might induce kidney injury by paracrine release of inflammatory factors. Yet, cellular senescence may be renoprotective during development and in some models of renal diseases, reflecting the yin/yang duality of cellular senescence. This review provides an overview of the role of this emerging player in renal injury, with emphasis on new findings of cellular senescence.