Histone Deacetylases Cooperate with NF-κB to Support the Immediate Migratory Response after Zebrafish Pronephros Injury

Acute kidney injury (AKI) is commonly associated with severe human diseases, and often worsens the outcome in hospitalized patients. The mammalian kidney has the ability to recover spontaneously from AKI; however, little progress has been made in the development of supportive treatments. Increasing evidence suggest that histone deacetylases (HDAC) and NF-κB promote the pathogenesis of AKI, and inhibition of Hdac activity has a protective effect in murine models of AKI. However, the role of HDAC at the early stages of recovery is unknown. We used the zebrafish pronephros model to study the role of epigenetic modifiers in the immediate repair response after injury to the tubular epithelium. Using specific inhibitors, we found that the histone deacetylase Hdac2, Hdac6, and Hdac8 activities are required for the repair via collective cell migration. We found that hdac6, hdac8, and nfkbiaa expression levels were upregulated in the repairing epithelial cells shortly after injury. Depletion of hdac6, hdac8, or nfkbiaa with morpholino oligonucleotides impaired the repair process, whereas the combined depletion of all three genes synergistically suppressed the recovery process. Furthermore, time-lapse video microscopy revealed that the lamellipodia and filopodia formation in the flanking cells was strongly reduced in hdac6-depleted embryos. Our findings suggest that Hdac activity and NF-κB are synergistically required for the immediate repair response in the zebrafish pronephros model of AKI, and the timing of HDAC inhibition might be important in developing supportive protocols in the human disease.     

Protective Effect of D-Panthenol in Rhabdomyolysis-Induced Acute Kidney Injury

We investigated the nephroprotective effect of D-panthenol in rhabdomyolysis-induced acute kidney injury (AKI). Adult male Wistar rats were injected with 50% glycerol solution to induce rhabdomyolysis. Animals with rhabdomyolysis were injected with D-panthenol (200 mg/kg) for 7 days. On day 8, we examined AKI markers, renal histology, antioxidant capacity, and protein glutathionylation in kidneys to uncover mechanisms of D-panthenol effects. Rhabdomyolysis kidneys were shown to have pathomorphological alterations (mononuclear infiltration, dilatation of tubules, and hyaline casts in Henle’s loops and collecting ducts). Activities of skeletal muscle damage markers (creatine kinase and lactate dehydrogenase) increased, myoglobinuria was observed, and creatinine, BUN, and pantetheinase activity in serum and urine rose. Signs of oxidative stress in the kidney tissue of rhabdomyolysis rats, increased levels of lipid peroxidation products, and activities of antioxidant enzymes (SOD, catalase, and glutathione peroxidase) were all alleviated by administration of D-panthenol. Its application improved kidney morphology and decreased AKI markers. Mechanisms of D-panthenol’s beneficial effects were associated with an increase in total coenzyme A levels, activity of Krebs cycle enzymes, and attenuation of protein glutathionylation. D-Panthenol protects kidneys from rhabdomyolysis-induced AKI through antioxidant effects, normalization of mitochondrial metabolism, and modulation of glutathione-dependent signaling.     

Noninvasive Diagnostics of Renal Amyloidosis: Current State and Perspectives

Amyloidoses is a group of diseases characterized by the accumulation of abnormal proteins (called amyloids) in different organs and tissues. For systemic amyloidoses, the disease is related to increased levels and/or abnormal synthesis of certain proteins in the organism due to pathological processes, e.g., monoclonal gammopathy and chronic inflammation in rheumatic arthritis. Treatment of amyloidoses is focused on reducing amyloidogenic protein production and inhibition of its aggregation. Therapeutic approaches critically depend on the type of amyloidosis, which underlines the importance of early differential diagnostics. In fact, the most accurate diagnostics of amyloidosis and its type requires analysis of a biopsy specimen from the disease-affected organ. However, absence of specific symptoms of amyloidosis and the invasive nature of biomaterial sampling causes the late diagnostics of these diseases, which leads to a delayed treatment, and significantly reduces its efficacy and patient survival. The establishment of noninvasive diagnostic methods and discovery of specific amyloidosis markers are essential for disease detection and identification of its type at earlier stages, which enables timely and targeted treatment. This review focuses on current approaches to the diagnostics of amyloidoses, primarily with renal involvement, and research perspectives in order to design new specific tests for early diagnosis.     

Critical Overview of Hepatic Factors That Link Non-Alcoholic Fatty Liver Disease and Acute Kidney Injury: Physiology and Therapeutic Implications

Non-alcoholic fatty liver disease (NAFLD) is defined as a combination of a group of progressive diseases, presenting different structural features of the liver at different stages of the disease. According to epidemiological surveys, as living standards improve, the global prevalence of NAFLD increases. Acute kidney injury (AKI) is a class of clinical conditions characterized by a rapid decline in kidney function. NAFLD and AKI, as major public health diseases with high prevalence and mortality, respectively, worldwide, place a heavy burden on societal healthcare systems. Clinical observations of patients with NAFLD with AKI suggest a possible association between the two diseases. However, little is known about the pathogenic mechanisms linking NAFLD and AKI, and the combination of the diseases is poorly treated. Previous studies have revealed that liver-derived factors are transported to distal organs via circulation, such as the kidney, where they elicit specific effects. Of note, while NAFLD affects the expression of many hepatic factors, studies on the mechanisms whereby NAFLD mediates the generation of hepatic factors that lead to AKI are lacking. Considering the unique positioning of hepatic factors in coordinating systemic energy metabolism and maintaining energy homeostasis, we hypothesize that the effects of NAFLD are not only limited to the structural and functional changes in the liver but may also involve the entire body via the hepatic factors, e.g., playing an important role in the development of AKI. This raises the question of whether analogs of beneficial hepatic factors or inhibitors of detrimental hepatic factors could be used as a treatment for NAFLD-mediated and hepatic factor-driven AKI or other metabolic disorders. Accordingly, in this review, we describe the systemic effects of several types of hepatic factors, with a particular focus on the possible link between hepatic factors whose expression is altered under NAFLD and AKI. We also summarize the role of some key hepatic factors in metabolic control mechanisms and discuss their possible use as a preventive treatment for the progression of metabolic diseases.     

Effect of Copper on the Function of Isolated Porcine Kidneys Stored Using Simple Hypothermia

Renal ischemia in the peri-transplant period causes a number of changes that adversely affect the initiation of normal vital functions in grafts after transplantation. To minimise the extent of ischemic damage, organs are stored in preservation fluid. The components of the fluid are supposed to ensure stabilisation of the cell cytoskeleton, protect against oxygen free radicals, reduce cell swelling, and ensure endothelial cell integrity. The aim of this study was to analyse the protective effect of Cu²⁺, as a component of Biolasol preservative fluid, in the prevention of nephron damage occurring during the graft storage period. Analyses of the effectiveness of copper in the presence of prolactin added to Biolasol fluid were also carried out. Forty isolated pig slaughter kidneys were used in the study, avoiding the use of laboratory animals. The kidneys were stored using simple hypothermia. After 2 h and 48 h of graft storage, selected biochemical indicators of renal function were determined in the collected perfusates. The addition of Cu²⁺ at a dose of 1 µg/L to the composition of Biolasol fluid was found to affect the generation of ischemic damage in the isolated pig kidney. The intensity of the occurrence of these processes is exacerbated by the presence of prolactin at a dose of 0.1 µg/L.     

Sodium-Glucose Cotransporter-2 Inhibitors—Miracle Drugs for the Treatment of Chronic Kidney Disease Irrespective of the Diabetes Status: Lessons from the Dedicated Kidney Disease-Focused CREDENCE and DAPA-CKD Trials

Diabetic kidney disease (DKD) is the leading cause of chronic kidney disease (CKD) and end-stage kidney disease worldwide. In Japan, the proportion of new patients requiring dialysis due to DKD has remained unchanged over the past five years. Early diagnosis and treatment are extremely important for the prevention of DKD progression. Albuminuria is the most promising biomarker currently available for diagnosing DKD and predicting its prognosis at an early stage; however, it has relatively poor specificity and sensitivity for DKD. Measuring the serum levels of tumor necrosis factor receptors (TNFRs; TNFR1 and TNFR2) is an alternative for predicting the prognosis of patients with CKD, irrespective of their diabetes status. Cardiorenal risk factor management and renin–angiotensin system inhibitor usage are effective in slowing the DKD progression, although the residual risk remains high in patients with DKD. Recently, two classes of antihyperglycemic agents, sodium–glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 receptor agonists, in addition to nonsteroidal selective mineralocorticoid receptor antagonists, which are less potent blood pressure-lowering and potassium-sparing agents, have emerged as cardiorenal disease-modifying therapies for preventing the DKD progression. This review focused on the SGLT2 inhibitor-based therapeutic strategies that have demonstrated cardiorenal benefits in patients with type 2 diabetes.     

Metabolomic Profiling of Plasma,Urine, and Saliva of Kidney Transplantation Recipients

Kidney biopsy is commonly used to diagnose kidney transplant dysfunction after transplantation. Therefore, the development of minimally invasive and quantitative methods to evaluate kidney function in transplant recipients is necessary. Here, we used capillary electrophoresis-mass spectrometry to analyze the biofluids collected from transplant recipients with impaired (Group I, n = 31) and stable (Group S, n = 19) kidney function and from donors (Group D, n = 9). Metabolomics analyses identified and quantified 97 metabolites in plasma, 133 metabolites in urine, and 108 metabolites in saliva. Multivariate analyses revealed apparent differences in the metabolomic profiles of the three groups. In plasma samples, arginine biosynthesis and purine metabolism between the I and S Groups differed. In addition, considerable differences in metabolomic profiles were observed between samples collected from participants with T cell-mediated rejection (TCR), antibody-mediated rejection, and other kidney disorders (KD). The metabolomic profiles in the three types of biofluids showed different patterns between TCR and KD, wherein 3-indoxyl sulfate showed a significant increase in TCR consistently in both plasma and urine samples. These results suggest that each biofluid has different metabolite features to evaluate kidney function after transplantation and that 3-indoxyl sulfate could predict acute rejection.     

Calorie Restriction Provides Kidney Ischemic Tolerance in Senescence-Accelerated OXYS Rats

Kidney diseases belong to a group of pathologies, which are most common among elderly people. With age, even outwardly healthy organisms start to exhibit some age-related changes in the renal tissue, which reduce the filtration function of kidneys and increase the susceptibility to injury. The therapy of acute kidney injury (AKI) is aggravated by the absence of targeted pharmacotherapies thus yielding high mortality of patients with AKI. In this study, we analyzed the protective effects of calorie restriction (CR) against ischemic AKI in senescence-accelerated OXYS rats. We observed that CR afforded OXYS rats with significant nephroprotection. To uncover molecular mechanisms of CR beneficial effects, we assessed the levels of anti- and proapoptotic proteins of the Bcl-2 family, COX IV, GAPDH, and mitochondrial deacetylase SIRT-3, as well as alterations in total protein acetylation and carbonylation, mitochondrial dynamics (OPA1, Fis1, Drp1) and kidney regeneration pathways (PCNA, GDF11). The activation of autophagy and mitophagy was analyzed by LC3 II/LC3 I ratio, beclin-1, PINK-1, and total mitochondrial protein ubiquitination. Among all considered protective pathways, the improvement of mitochondrial functioning may be suggested as one of the possible mechanisms for beneficial effects of CR.     

Immune Responses to COVID-19 Vaccines in Patients with Chronic Kidney Disease and Lead Exposure

Literature data regarding the response rate to COVID-19 vaccination in chronic kidney disease (CKD) patients remain inconclusive. Furthermore, studies have reported a relationship between lead exposure and susceptibility to viral infections. This study examined immune responses to COVID-19 vaccines in patients with CKD and lead exposure. Between October and December 2021, 50 lead-exposed CKD patients received two doses of vaccination against COVID-19 at Chang Gung Memorial Hospital. Patients were stratified into two groups based on the median blood lead level (BLL): upper (≥1.30 μg/dL, n = 24) and lower (<1.30 μg/dL, n = 26) 50th percentile. The patients were aged 65.9 ± 11.8 years. CKD stages 1, 2, 3, 4 and 5 accounted for 26.0%, 20.0%, 22.0%, 8.0% and 24.0% of the patients, respectively. Patients in the lower 50th percentile of BLL had a lower proportion of CKD stage 5 than patients in the upper 50th percentile BLL group (p = 0.047). The patients in the lower 50th percentile BLL group also received a higher proportion of messenger RNA vaccines and a lower proportion of adenovirus-vectored vaccines than the patients in the upper 50th percentile BLL group (p = 0.031). Notably, the neutralizing antibody titers were higher in the lower 50th percentile than in the upper 50th percentile BLL group. Furthermore, the circulating levels of granulocyte-colony stimulating factor, interleukin-8, monocyte chemoattractant protein-1 and macrophage inflammatory protein-1α were higher in the upper 50th percentile than in the lower 50th percentile BLL group. Therefore, it was concluded that lead-exposed CKD patients are characterized by an impaired immune response to COVID-19 vaccination with diminished neutralizing antibodies and augmented inflammatory reactions.     

黄秋葵水提物对2型糖尿病大鼠血尿酸及肾功能的影响

目的:探讨黄秋葵水提物对2型糖尿病大鼠血尿酸水平及肾脏功能的影响。方法:将72只SD雄鼠随机分为正常对照组（8只）和2型糖尿病造模组（64只）,除正常对照组为普通饲料,其余均以高糖高脂饲料喂养。4周后,造模组大鼠腹腔注射链脲佐菌素（STZ）建立2型糖尿病动物模型。成模大鼠随机分为5组:糖尿病模型组、阳性对照组（0.64 g/kg·d-1降糖宁灌胃）、黄秋葵低、中、高剂量组（分别按每公斤体重给予0.78、1.56、2.60 g黄秋葵水提物添加到高糖高脂饲料中）,4周后,采集大鼠尿样,处死大鼠,称量肾脏重量以计算肾脏系数,同时测血尿酸、血肌酐和血尿素氮。结果:与糖尿病模型组比较,黄秋葵水提物高剂量组血尿酸水平降低（p<0.05）,低、中、高剂量组大鼠的血肌酐和血尿素氮均有不同程度的下降,但差异无统计学意义（p>0.05）。结论:适宜剂量的黄秋葵水提物可降低2型糖尿病大鼠血尿酸水平,其对肾脏的保护作用有待进一步研究。