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Objectives To compare sodium ( 23 Na) characteristics between native and transplanted kidneys using dual-tuned proton ( 1 H)/sodium MRI. Methods Six healthy volunteers and six renal transplant patients (3 normal function, 3 acute allograft rejection) were included. Proton/sodium MRI was obtained at 3 T using a dual-tuned coil. Signal to noise ratio (SNR), sodium concentration ([ 23 Na]) and cortico-medullary sodium gradient (CMSG) were measured. Reproducibility of [ 23 Na] measurement was also tested. SNR, [ 23 Na] and CMSG of the native and transplanted kidneys were compared. Results Proton and sodium images of kidneys were successfully acquired. SNR and [ 23 Na] measurements of the native kidneys were reproducible at two different sessions. [ 23 Na] and CMSG of the transplanted kidneys was significantly lower than those of the native kidneys: 153.5 ± 11.9 vs. 192.9 ± 9.6 mM ( P  = 0.002) and 8.9 ± 1.5 vs. 10.5 ± 0.9 mM/mm ( P  = 0.041), respectively. [ 23 Na] and CMSG of the transplanted kidneys with normal function vs. acute rejection were not statistically different. Conclusions Sodium quantification of kidneys was reliably performed using proton/sodium MRI. [ 23 Na] and CMSG of the transplanted kidneys were lower than those of the native kidneys, but without a statistically significant difference between patients with or without renal allograft rejection. Key Points • Dual-tuned proton/sodium RF coil enables co-registered proton and sodium MRI . • Structural and sodium biochemical property can be acquired by dual-tuned proton/sodium MRI . • Sodium and sodium gradient of kidneys can be measured by dual-tuned MRI . • Sodium concentration was lower in transplanted kidneys than in native kidneys . • Sodium gradient of transplanted kidneys was lower than for native kidneys .

Inhibition of sodium glucose cotransporter 2 (SGLT2) has been reported as a new therapeutic strategy for treating diabetes. However, the effect of SGLT2 inhibitors on the kidney is unknown. In addition, whether SGLT2 inhibitors have an anti-inflammatory or antioxidative stress effect is still unclear. In this study, to resolve these issues, we evaluated the effects of the SGLT2 inhibitor, dapagliflozin, using a mouse model of type 2 diabetes and cultured proximal tubular epithelial (mProx24) cells. Male db/db mice were administered 0.1 or 1.0 mg/kg of dapagliflozin for 12 weeks. Body weight, blood pressure, blood glucose, hemoglobin A1c, albuminuria and creatinine clearance were measured. Mesangial matrix accumulation and interstitial fibrosis in the kidney and pancreatic β-cell mass were evaluated by histological analysis. Furthermore, gene expression of inflammatory mediators, such as osteopontin, monocyte chemoattractant protein-1 and transforming growth factor-β, was evaluated by quantitative reverse transcriptase-PCR. In addition, oxidative stress was evaluated by dihydroethidium and NADPH oxidase 4 staining. Administration of 0.1 or 1.0 mg/kg of dapagliflozin ameliorated hyperglycemia, β-cell damage and albuminuria in db/db mice. Serum creatinine, creatinine clearance and blood pressure were not affected by administration of dapagliflozin, but glomerular mesangial expansion and interstitial fibrosis were suppressed in a dose-dependent manner. Dapagliflozin treatment markedly decreased macrophage infiltration and the gene expression of inflammation and oxidative stress in the kidney of db/db mice. Moreover, dapagliflozin suppressed the high-glucose-induced gene expression of inflammatory cytokines and oxidative stress in cultured mProx24 cells. These data suggest that dapagliflozin ameliorates diabetic nephropathy by improving hyperglycemia along with inhibiting inflammation and oxidative stress.

Tolvaptan, a vasopressin type 2 receptor antagonist initially developed to increase free-water diuresis, has been approved for the treatment of autosomal dominant polycystic kidney disease in multiple countries. Furthermore, tolvaptan has been shown to improve the renal functions in rodent models of chronic kidney disease (CKD); however, the underlying molecular mechanisms remain unknown. CKD is characterized by increased levels of oxidative stress, and an antioxidant transcription factor—nuclear factor erythroid 2-related factor 2 (Nrf2)—has been gaining attention as a therapeutic target. Therefore, we investigated the effects of tolvaptan and a well-known Nrf2 activator, bardoxolone methyl (BARD) on Nrf2. To determine the role of tolvaptan, we used a renal cortical collecting duct (mpkCCD) cell line and mouse kidneys. Tolvaptan activated Nrf2 and increased mRNA and protein expression of antioxidant enzyme heme oxygenase-1 (HO-1) in mpkCCD cells and the outer medulla of mouse kidneys. In contrast to BARD, tolvaptan regulated the antioxidant systems via a unique mechanism. Tolvaptan activated the Nrf2/HO-1 antioxidant pathway through phosphorylation of protein kinase RNA-like endoplasmic reticulum kinase (PERK). As a result, tolvaptan and BARD could successfully generate synergistic activating effects on Nrf2/HO-1 antioxidant pathway, suggesting that this combination therapy can contribute to the treatment of CKD.

The epidemic of chronic kidney disease in Nicaragua (Mesoamerican nephropathy) has been linked with recurrent dehydration. Here we tested whether recurrent dehydration may cause renal injury by activation of the polyol pathway, resulting in the generation of endogenous fructose in the kidney that might subsequently induce renal injury via metabolism by fructokinase. Wild-type and fructokinase-deficient mice were subjected to recurrent heat-induced dehydration. One group of each genotype was provided water throughout the day and the other group was hydrated at night, after the dehydration. Both groups received the same total hydration in 24h. Wild-type mice that received delayed hydration developed renal injury, with elevated serum creatinine, increased urinary NGAL, proximal tubular injury, and renal inflammation and fibrosis. This was associated with activation of the polyol pathway, with increased renal cortical sorbitol and fructose levels. Fructokinase-knockout mice with delayed hydration were protected from renal injury. Thus, recurrent dehydration can induce renal injury via a fructokinase-dependent mechanism, likely from the generation of endogenous fructose via the polyol pathway. Access to sufficient water during the dehydration period can protect mice from developing renal injury. These studies provide a potential mechanism for Mesoamerican nephropathy.

Oxidative stress is implicated in human diseases. Some of the oxidative pathways are harbored in the mitochondria. NAD(P)H oxidases have been identified not only in phagocytic but also in somatic cells. Nox4 is the most ubiquitous of these oxidases and is a major source of reactive oxygen species (ROS) in many cell types and in kidney tissue of diabetic animals. We generated specific Nox4 antibodies, and found that Nox4 localizes to mitochondria. (i) Immunoblot analysis in cultured mesangial cells and kidney cortex revealed that Nox4 is present in crude mitochondria, in mitochondria-enriched heavy fractions, and in purified mitochondria; (ii) immunofluorescence confocal microscopy also revealed that Nox4 localizes with the mitochondrial marker Mitotracker; and (iii) the mitochondrial localization prediction program MitoProt indicated that the probability score for Nox4 is identical to mitochondrial protein cytochrome c oxidase subunit IV. We also show that in purified mitochondria, siRNA-mediated knockdown of Nox4 significantly reduces NADPH oxidase activity in pure mitochondria and blocks glucose-induced mitochondrial superoxide generation. In a rat model of diabetes, mitochondrial Nox4 expression is increased in kidney cortex. Our data provide evidence that a functional Nox4 is present and regulated in mitochondria, indicating the existence of a previously undescribed source of ROS in this organelle.

Calcium oxalate (CaOx) stones are prevalent in urinary tract stone disease. While their formation can be induced in rats by administering ethylene glycol and vitamin D, the initial nucleation and formation processes are unclear. Here, we aimed to determine where CaOx crystals initially form, examine the associated histological and morphological changes, and clarify the genes whose expression varies at those sites and their function. Male Wistar rats were divided into four groups: control, ethylene glycol, vitamin D, and ethylene glycol plus vitamin D (EG + VitD). Crystal development locations were mapped on kidney tissue sections, and the initial crystal site distribution was revealed. CaOx crystal formation was observed only in the EG + VitD group kidneys, predominantly in the proximal tubules in the outer renal cortex. The tubular luminal area was significantly increased ( P  < 0.05), especially in proximal tubules, correlating with the crystal occurrence number. Moreover, aquaporin1 and calbindin staining identified the tubular segments hosting initial crystal formation, and the tubular dilation was calculated. DNA microarray was analyzed on cortical and medullary kidney tissues to detect stone formation-related gene expression changes. Genes with variable expression were further examined using RT-PCR and immunohistochemistry to analyze their distribution. FGA, Slc7a9, Slc7a7, and TRPV5 were significantly upregulated in the renal cortex, and FGA was significantly upregulated in the proximal tubules, consistent with the crystal formation sites. Early phase crystallization primarily occurs in the proximal tubules. In silico analysis, FGA protein has multiple oxalic acid-binding sites, making it a potential new factor promoting CaOx crystal formation.

The Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) represent family of structurally-related eukaryotic transcription factors which regulate diverse array of cellular processes including immunological responses, inflammation, apoptosis, growth & development. Increased expression of NF-kB has often been seen in many diverse diseases, suggesting the importance of genomic deregulation to disease pathophysiology. In the present study we focused on acute kidney injury (AKI), which remains one of the major risk factor showing a high rate of mortality and morbidity. The pathology associated with it, however, remains incompletely known though inflammation has been reported to be one of the major risk factor in the disease pathophysiology. The role of NF-kB thus seemed pertinent. In the present study we show that high dose of folic acid (FA) induced acute kidney injury (AKI) characterized by elevation in levels of blood urea nitrogen & serum creatinine together with extensive tubular necrosis, loss of brush border and marked reduction in mitochondria. One of the salient observations of this study was a coupled increase in the expression of renal, relA, NF-kB2, and p53 genes and proteins during folic acid induced AKI (FA AKI). Treatment of mice with NF-kB inhibitor, pyrrolidine dithio-carbamate ammonium (PDTC) lowered the expression of these transcription factors and ameliorated the aberrant renal function by decreasing serum creatinine levels. In conclusion, our results suggested that NF-kB plays a pivotal role in maintaining renal function that also involved regulating p53 levels during FA AKI.

Glyphosate (GP) and its derivatives are present in almost all environments and suspected to induce acute and chronic kidney injuries. This public health issue is relatively underexplored. We therefore conducted an investigation on rats and tubular HK2 cells cultured for 24 h to determine whether GP’s and Roundup’s® (RU) potential renal toxicity might be related to mitochondrial respiration impairment and the increased production of hydrogen peroxide (H2O2) in both the renal cortex and medulla (involved in filtration and reabsorption, respectively) using a high-resolution oxygraph (Oxygraph-2K, Oroboros instruments). GP alone decreased maximal uncoupled mitochondrial respiration in the medulla (−14.2%, p = 0.02). RU decreased mitochondrial respiratory chain complexes I and I + II and the maximal respiratory capacity both in the renal cortex (−13.5%, p = 0.04; −20.1%, p = 0.009; and −14.7%, p = 0.08, respectively) and in the medulla for OXPHOS I + II (80.82 ± 7.88 vs. 61.03 ± 7.67 pmol/(s·mL), −24.5%, p = 0.003). Similarly, in HK2 cells, the decrease in OXPHOS CI + II was greater after RU (65.87 ± 1.30 vs. 51.82 ± 3.50 pmol/(s·mL), −21.3%, p = 0.04) compared to GP. Increased H2O2 production was mainly observed after RU in the medulla (+14.3% in OXPHOS CI + II, p = 0.04) and in HK2 cells (+19% in OXPHOS CI + II, p = 0.02). In conclusion, although the medulla might be more prone to GP-related mitochondrial damage, RU toxicity was greater in both the renal cortex and medulla and in cultured tubular HK2 cells. Enhancing mitochondrial respiration and reducing oxidative stress might favor the prevention of or reduction in such worldwide-used herbicides’ deleterious effects on the kidneys.

Prior studies have established the important role of extracellular signal-regulated kinase 1/2 (ERK1/2) as a mediator of acute kidney injury (AKI). We demonstrated rapid ERK1/2 activation induced renal dysfunction following ischemia/reperfusion (IR)-induced AKI and downregulated the mitochondrial biogenesis (MB) regulator, peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) in mice. In this study, ERK1/2 regulation of cellular nicotinamide adenine dinucleotide (NAD) and PGC-1α were explored. Inhibition of ERK1/2 activation during AKI in mice using the MEK1/2 inhibitor, trametinib, attenuated renal cortical oxidized NAD (NAD + ) depletion. The rate-limiting NAD biosynthesis salvage enzyme, NAMPT, decreased following AKI, and this decrease was prevented by ERK1/2 inhibition. The microRNA miR34a decreased with the inhibition of ERK1/2, leading to increased NAMPT protein. Mice treated with a miR34a mimic prevented increases in NAMPT protein in the renal cortex in the presence of ERK1/2 inhibition. In addition, ERK1/2 activation increased acetylated PGC-1α, the less active form, whereas inhibition of ERK1/2 activation prevented an increase in acetylated PGC-1α after AKI through SIRT1 and NAD + attenuation. These results implicate IR-induced ERK1/2 activation as an important contributor to the downregulation of both PGC-1α and NAD + pathways that ultimately decrease cellular metabolism and renal function. Inhibition of ERK1/2 activation prior to the initiation of IR injury attenuated decreases in PGC-1α and NAD + and prevented kidney dysfunction.

Diabetic nephropathy (DN) is a primary cause of end-stage renal disease. Despite the beneficial effects of astragaloside IV (AS)-IV on renal disease, the underlying mechanism of its protective effects against DN has not been fully determined. The aims of the present study were to assess the effects of AS-IV against DN in db/db mice and to explore the mechanism of AS-IV involving the NLR family pyrin domain containing 3 (NLRP3), caspase-1 and interleukin (IL)-1β pathways. The 8-week-old db/db mice received 40 mg/kg AS-IV once a day for 12 weeks via intragastric administration. Cultured mouse podocytes were used to further confirm the underlying mechanism in vitro. AS-IV effectively reduced weight gain, hyperglycemia and the serum triacylglycerol concentration in db/db mice. AS-IV also reduced urinary albumin excretion, urinary albumin-to-creatinine ratio and creatinine clearance rate, as well as improved renal structural changes, accompanied by the upregulation of the podocyte markers podocin and synaptopodin. AS-IV significantly inhibited the expression levels of NLRP3, caspase-1 and IL-1β in the renal cortex, and reduced the serum levels of tumor necrosis factor (TNF)-α and monocyte chemoattractant protein-1. In high glucose-induced podocytes, AS-IV significantly improved the expression levels of NLRP3, pro-caspase-1 and caspase-1, and inhibited the cell viability decrease in a dose-dependent manner, while NLRP3 overexpression eliminated the effect of AS-IV on podocyte injury and the inhibition of the NLRP3 and caspase-1 pathways. The data obtained from in vivo and in vitro experiments demonstrated that AS-IV ameliorated renal functions and podocyte injury and delayed the development of DN in db/db mice via anti-NLRP3 inflammasome-mediated inflammation.