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We used retrograde transneuronal transport of rabies virus from the rat kidney to identify the areas of the cerebral cortex that are potential sources of central commands for the neural regulation of this organ. Our results indicate that multiple motor and nonmotor areas of the cerebral cortex contain output neurons that indirectly influence kidney function. These cortical areas include the primary motor cortex (M1), the rostromedial motor area (M2), the primary somatosensory cortex, the insula and other regions surrounding the rhinal fissure, and the medial prefrontal cortex. The vast majority of the output neurons from the cerebral cortex were located in two cortical areas, M1 (68%) and M2 (15%). If the visceromotor functions of M1 and M2 reflect their skeletomotor functions, then the output to the kidney from each cortical area could make a unique contribution to autonomic control. The output from M1 could add precision and organ-specific regulation to descending visceromotor commands, whereas the output from M2 could add anticipatory processing which is essential for allostatic regulation. We also found that the output from M1 and M2 to the kidney originates predominantly from the trunk representations of these two cortical areas. Thus, a map of visceromotor representation appears to be embedded within the classic somatotopic map of skeletomotor representation.
Chronic kidney disease (CKD) affects kidney cancer patients' mortality. However, the underlying mechanism remains unknown. M2-like macrophages have pro-tumor functions, also exist in injured kidney, and promote kidney fibrosis. Thus, it is suspected that M2-like macrophages in injured kidney induce the pro-tumor microenvironment leading to kidney cancer progression. We found that M2-like macrophages present in the injured kidney promoted kidney cancer progression and induced resistance to anti-PD1 antibody through its pro-tumor function and inhibition of CD8+ T cell infiltration. RNA-seq revealed Slc7a11 was upregulated in M2-like macrophages. Inhibition of Slc7a11 with sulfasalazine inhibited the pro-tumor function of M2-like macrophages and synergized with anti-PD1 antibody. Moreover, SLC7A11-positive macrophages were associated with poor prognosis among kidney cancer patients. Collectively, this study dissects the characteristic microenvironment in the injured kidney that contributed to kidney cancer progression and anti-PD1 antibody resistance. This insight offers promising combination therapy with anti-PD1 antibody and macrophage targeted therapy.
The mechanism of cadmium (Cd)-induced damage in the mammalian proximal tubule that is manifested by defects in reabsorption of various compounds, is poorly understood. A vacuolar H(+)-ATPase (V-ATPase) in proximal tubule (PT) brush border and intracellular vesicles may be affected by Cd, and this may influence intracellular vesicle trafficking and reabsorption of the filtered proteins. We studied the effects of Cd on V-ATPase and endocytosis in rat renal PT in vivo and on acidification mechanisms in isolated renal cortical organelles in vitro. The V-ATPase activity in brush border membrane (BBM) from Cd-intoxicated rats was 40% lower compared to that in control animals. Immunofluorescence studies in cortical tissue sections and Western blot studies in BBM from Cd-treated rats showed a strongly decreased abundance of the 31 kDa and 70 kDa V-ATPase subunits. Functional studies in vivo showed a dramatically diminished endocytosis of fluorescein-labeled dextran in PT cells from Cd-treated animals, whereas morphological studies revealed a loss of endocytic invaginations and subapical vesicles in the same cells. In studies in vitro, Cd inhibited V-ATPase activity in a concentration- and time-dependent manner in both BBM and endocytic vesicles, whereas in endocytic vesicles, Cd inhibited ATP-driven intravesicular acidification and accelerated the dissipation of transmembrane pH gradients. We conclude that Cd may impair acidification in cell organelles by (a) causing a loss of V-ATPase protein in their limiting membranes, (b) inhibiting the intrinsic V-ATPase activity, and (c) dissipating the transmembrane pH gradient. This may inhibit endocytosis of filtered proteins and impair vesicle-mediated recycling of some membrane transporters, thus contributing to the loss of reabsorptive capacity of the PT.
(1) Background: We previously showed Na/H exchange regulatory factor 1 (NHERF1) loss resulted in increased susceptibility to cisplatin nephrotoxicity. NHERF1-deficient cultured proximal tubule cells and proximal tubules from NHERF1 knockout (KO) mice exhibit altered mitochondrial protein expression and poor survival. We hypothesized that NHERF1 loss results in changes in metabolic pathways and/or mitochondrial dysfunction, leading to increased sensitivity to cisplatin nephrotoxicity. (2) Methods: Two to 4-month-old male wildtype (WT) and KO mice were treated with vehicle or cisplatin (20 mg/kg dose IP). After 72 h, kidney cortex homogenates were utilized for metabolic enzyme activities. Non-treated kidneys were used to isolate mitochondria for mitochondrial respiration via the Seahorse XF24 analyzer. Non-treated kidneys were also used for LC-MS analysis to evaluate kidney ATP abundance, and electron microscopy (EM) was utilized to evaluate mitochondrial morphology and number. (3) Results: KO mouse kidneys exhibit significant increases in malic enzyme and glucose-6 phosphate dehydrogenase activity under baseline conditions but in no other gluconeogenic or glycolytic enzymes. NHERF1 loss does not decrease kidney ATP content. Mitochondrial morphology, number, and area appeared normal. Isolated mitochondria function was similar between WT and KO. Conclusions: KO kidneys experience a shift in metabolism to the pentose phosphate pathway, which may sensitize them to the oxidative stress imposed by cisplatin.
It is believed that the vasopressinergic system plays an important role in the pathogenesis of chronic kidney disease (CKD). The aim of this study was to evaluate the effect of CKD on changes in vasopressin system expression in the kidney cortex in rats with nephrectomy. The study was performed on 4 groups of Sprague Dawley (SPRD) rats: a control group (CN), 1/2 nephrectomy (N1/2), 2/3 nephrectomy (N2/3), and 5/6 nephrectomy (N5/6). Blood and the kidney cortex were collected to evaluate plasma copeptin concentrations and mRNA expressions of V1a vasopressin receptors (V1aR) and V2 vasopressin receptors (V2R) and V1aR, V2R, and aquaporin 2 (AQP2) protein levels. V1aR and V2R mRNA expression in the kidney cortex was significantly lower in the CN group compared with the other groups. In contrast, the V1aR, V2R, and AQP2 protein levels were significantly higher in the CN group compared with all of the nephrectomized groups. Plasma copeptin concentration was significantly lower in the CN group than in the nephrectomized groups. CKD caused significant changes in the expression of the vasopressinergic system. Further research is needed to explain the mechanisms of the impact of the vasopressinergic system on the kidney in CKD.
Aldehyde reductase (EC 1.1.1.2) has been regarded so far as an exclusively cytosolic enzyme. The present investigation shows that mitochondria of rat liver, kidney cortex and, tentatively, heart also contain an enzyme catalyzing oxidation of NADPH by aldehydes, p-nitrobenzaldehyde, methylglyoxal and glyceraldehyde. Activity of the mitochondrial enzyme can only be measured after the organelles are disrupted by sonication or solubilized with nonionic detergents. Mitochondrial aldehyde reductase activity contributed to about 4.6% and 2.5% of the total cellular activity in liver and kidney cortex, respectively. However, the specific activity in liver mitochondria was about one third and in kidney cortex mitochondria one tenth of that in the cytosol of the corresponding organ. The mitochondrial enzyme resembled the cytosolic one by its absolute specificity towards NADPH as the electron donor, a similar profile of aldehydic electron acceptors and identical Km values. Mitochondrial aldehyde reductase differed from the cytosolic enzyme by low sensitivity to known inhibitors of cytosolic aldehyde reductase, AL-1576, AL-4114 and ONO-2235. In liver, about 60% of the mitochondrial activity was tightly bound to the membranes whereas about 40% was present in the mitochondrial matrix. The membrane-bound activity was inactivated by digestion of mitoplasts with trypsin, alpha-chymotrypsin or papain, thus pointing to exposition of the substrate-binding site at the external surface of the inner membrane. On the other hand, latency of the enzyme in intact mitochondria indicates that the NADPH-binding site is located at the inner surface. These data provide the first direct evidence for the existence of aldehyde reductase in mitochondria of some rat tissues.
The presence of multinucleated cells has never been demonstrated in renal tissue, although, polyploid cells were recently observed in the tubules of normal and pathological human kidney. Therefore, the aim of the present study is to identify and quantify, by electron microscopy, multinucleated cells in the cortical tissue of normal human kidney i.e., in the three compartments of renal tubule: the proximal tubule (PT), the distal tubule (DT), and the collecting duct (CD), as well as, in the glomerulus (podocytes). The percentage of the multinucleated cells observed was 5% (95%CI: 3.6%-6.7%) in renal cortical tubules with distribution in each tubular compartment of 6% in PT, 4% in DT and 3% in CD with no statistically significant difference in the distribution of multinucleated cells according to tubular compartments. Four percent of analysed podocytes (in total 149 podocytes) were multinucleated (95%CI: 1.5%-8.6%). In conclusion, multinucleated cells were identified and quantified in functionally normal kidneys, as previously demonstrated in other organs such as the liver.
Although ischemia is the leading cause of acute renal failure in human, there is little information on the remodeling the kidney endothelium matrix during ischemic injury. In this study, we investigated the activity and expression of MMP-2 and MMP-9, in an isolated endothelial fraction following an acute in vivo reversible ischemia induced in rats by vascular clamping. Ischemia increased serum creatinine levels 1.4-fold, hallmark of acute renal failure. Isolation of the endothelial cell fraction was performed by affinity chromatography using an anti-PECAM-1 antibody. The isolated fraction was assessed by Western blotting analysis of endothelial cell markers. The positively selected fractions were enriched in the endothelial markers eNOS and PECAM-1 by 128-fold and 44-fold, respectively. Gelatin zymography showed that ischemia strongly stimulated proteolytic activity of proMMP-2 (1.8-fold), proMMP-9 (3-fold) and MMP-9 (4-fold) in the endothelial fractions. Western blot analysis indicated that TIMP-2 protein level increased by 3.2-fold in the endothelial fractions during ischemia. Surprisingly, TIMP-1 was absent from the endothelial preparations but was easily detected in the non-endothelial cells. Levels of the endocytic receptor LRP were increased by 2-fold during ischemia in the endothelial fractions. Occludin, a known in vivo MMP-9 substrate, was partly degraded in the endothelial fractions during ischemia, suggesting that the MMP-9 which was upregulated during ischemia was functional. These data suggest that ischemia in kidney could lead to the degradation of the vascular basement membrane and to increased permeability. This suggests new therapeutic approaches for ischemic pathologies by targeting MMP-9 and its regulators.
Acute fetal hypoxia is a form of fetal stress that stimulates renal vasoconstriction and ischaemia as a consequence of the physiological redistribution of combined ventricular output. Because of the potential ischaemia-reperfusion injury to the kidney, we hypothesized that it would respond to hypoxia with an increase in the expression of inflammatory genes, and that ketamine (an N-methyl-D-aspartate receptor antagonist) would reduce or block this response. Hypoxia was induced for 30 min in chronically catheterized fetal sheep (125 ± 3 days), with or without ketamine (3 mg kg(-1)) administered intravenously to the fetus 10 min prior to hypoxia. Gene expression in fetal kidney cortex collected 24 h after the onset of hypoxia was analysed using ovine Agilent 15.5k array and validated with qPCR and immunohistochemistry in four groups of ewes: normoxic control, normoxia + ketamine, hypoxic control and hypoxia + ketamine (n = 3-4 per group). Significant differences in gene expression between groups were determined with t-statistics using the limma package for R (P ≤ 0.05). Enriched biological processes for the 427 upregulated genes were immune and inflammatory responses and for the 946 downregulated genes were metabolic processes. Ketamine countered the effects of hypoxia on upregulated immune/inflammatory responses as well as the downregulated metabolic responses. We conclude that our transcriptomics modelling predicts that hypoxia activates inflammatory pathways and reduces metabolism in the fetal kidney cortex, and ketamine blocks or ameliorates this response. The results suggest that ketamine may have therapeutic potential for protection from ischaemic renal damage.
Growing evidence suggests that polysaccharides from traditional Chinese medicine positively affect diabetic kidney disease (DKD) mainly through modulating gut microbiota. Previously, we demonstrated that supplementation with the polysaccharide from Moutan Cortex (MC-Pa) alleviated DKD in rats. The study intends to investigate the dynamic modulation of MC-Pa on DKD from the gut microbiota perspective. The DKD rat model was induced by a high-fat and high-sugar diet combined with streptozotocin (STZ). The rats were then supplemented with MC-Pa (80 and 160 mg/kg BW) for 12 weeks. The results showed that MC-Pa administration relieved hyperglycemia and renal injury in DKD rats. MC-Pa also reconstructed gut microbiota, improved intestinal barrier function, reduced serum proinflammatory mediators, and elevated the short-chain fatty acid (SCFAs) contents. In addition, the dynamics of Lactobacillus and Muribaculaceae_unclassified were in a dose- and time-dependent manner. Spearman correlation analysis found that a cluster of gut microbiota phyla and genera were significantly associated with DKD-related indicators. These results demonstrated that MC-Pa positively affected DKD rats by modulating gut microbiota dynamically and had potential as a prebiotic.
A number of imaging readout schemes are proposed for renal arterial spin labeling (ASL) to quantify kidney cortex perfusion, including gradient echo-based methods of balanced fast field echo (bFFE) and gradient-echo echo-planar imaging (GE-EPI), or spin echo-based schemes of spin-echo echo-planar imaging (SE-EPI) and turbo spin-echo (TSE). Here, we compare these two-dimensional (2D) imaging schemes to evaluate the optimal imaging scheme for pulsed ASL (PASL) assessment of human kidney cortex perfusion at 3 T. Ten healthy volunteers with normal renal function were scanned using each 2D multi-slice imaging scheme, in combination with a respiratory triggered flow-sensitive alternating inversion recovery (FAIR) ASL scheme on a 3 T Philips Achieva scanner. All volunteers returned for a second identical scan session within two weeks of the first scan session. Comparisons were made between the imaging schemes in terms of perfusion-weighted image (PWI) signal-to-noise ratio (SNR) and perfusion quantification, temporal SNR (tSNR), spatial coverage, and repeatability. For each imaging scheme, the renal cortex perfusion was calculated (bFFE: 276 ± 29 mL/100g/min, GE-EPI: 222 ± 18 mL/100g/min, SE-EPI: 201 ± 36 mL/100g/min, and TSE: 200 ± 20 mL/100g/min). Perfusion was found to be higher for GE-based readouts when compared with SE-based readouts, with significantly higher measured perfusion for the bFFE readout when compared with all other schemes (p < 0.05), attributed to the greater vascular signal present. Despite the PWI-SNR being significantly lower for SE-EPI when compared with all other schemes (p < 0.05), the SE-EPI readout gave the highest tSNR, and was found to be the most reproducible scheme for the assessment of kidney cortex, with a coefficient of variation (CoV) of 17.2%, whilst minimizing variability of the perfusion-weighted signal across slices for whole-kidney perfusion assessment. For the assessment of kidney cortex perfusion using 2D readout schemes, SE-EPI provides optimal tSNR, minimal variability across slices, and repeatable data acquired in a short scan time with low specific absorption rate.
Sepsis-induced acute kidney injury (AKI) can increase the mortality of critically ill patients and the incidence of chronic kidney disease in critically ill survivors. The main goal was to investigate the possible link between metabolic changes and sepsis-induced AKI development. The experimental animal model of sepsis-induced AKI was established by intraperitoneal injection of lipopolysaccharide in rats. Non-targeted metabolic screening of the renal cortex in the control and sepsis-induced AKI groups was carried out based on gas chromatography coupled with quadrupole time-of-flight mass spectrometry (GC-TOFMS) technology. The data between the two groups were analyzed by combining univariate and multivariate statistical methods, and the metabolites associated with AKI in rats with sepsis were screened. By examining the Kyoto Encyclopedia of Genes and Genomes (KEGG) database, altered metabolic pathways associated with acute renal injury in sepsis were identified. The cross validated scores plot of orthogonal partial least squares discriminant analysis (OPLS-DA) showed a distinct separation trend between the model and control groups in the profile of renal cortex metabolites, indicating a significant change in endogenous metabolites in the rat renal cortex. Further analysis and screening showed that 26 different metabolites were identified in the renal cortex between the two groups, mainly involving taurine and hypotaurine metabolism, pantothenic acid and CoA biosynthesis, phenylalanine metabolism, and other metabolic pathways. The metabolic disorders of taurine, pantothenic acid, and phenylalanine in the renal cortex are related to the development of acute renal injury in sepsis. Correcting these metabolic disorders is expected to prevent and treat sepsis-induced AKI.
Salt plays an essential role in the progression of chronic kidney disease and hypertension. However, the mechanisms underlying pathogenesis of salt-induced kidney damage remain largely unknown. Here, Sprague-Dawley rats, that underwent 5/6 nephrectomy (5/6Nx, a model of advanced kidney damage) or sham operation, were treated for 2 weeks with a normal or high-salt diet. We employed aTiO2 enrichment, iTRAQ labeling and liquid-chromatography tandem mass spectrometry strategy for proteomic and phosphoproteomic profiling of the renal cortex. We found 318 proteins differentially expressed in 5/6Nx group relative to sham group, and 310 proteins significantly changed in response to salt load in 5/6Nx animals. Totally, 1810 unique phosphopeptides corresponding to 550 phosphoproteins were identified. We identified 113 upregulated and 84 downregulated phosphopeptides in 5/6Nx animals relative to sham animals. Salt load induced 78 upregulated and 91 downregulated phosphopeptides in 5/6Nx rats. The differentially expressed phospholproteins are important transporters, structural molecules, and receptors. Protein-protein interaction analysis revealed that the differentially phosphorylated proteins in 5/6Nx group, Polr2a, Srrm1, Gsta2 and Pxn were the most linked. Salt-induced differential phosphoproteins, Myh6, Lmna and Des were the most linked. Altered phosphorylation levels of lamin A and phospholamban were validated. This study will provide new insight into pathogenetic mechanisms of chronic kidney disease and salt sensitivity.
The circulating L-3,4-dihydroxyphenylalanine, the drug of choice in the therapy of Parkinson's disease (PD), is efficiently extracted by kidney and converted to dopamine, known to control several renal functions. As: (i) in addition to liver, kidney is an important source of glucose in mammals and (ii) the action of this drug on renal gluconeogenesis has not yet been studied, the aim of the present investigation was to estimate the influence of L-3,4-dihydroxyphenylalanine metabolism on glucose formation in isolated kidney-cortex tubules incubated with various gluconeogenic substrates. The data indicate that a rapid intracellular degradation of L-3,4-dihydroxyphenylalanine and tyramine (at 100 and 200 microM concentrations) is accompanied by 25-40% decrease in glucose production from pyruvate, alanine + glycerol + octanoate and dihydroxyacetone due to augmented generation of hydrogen peroxide via monoamine oxidase B, resulting in a decline of glutathione redox state by 40%. Moreover, following inhibition of monoamine oxidase B by deprenyl or substitution of pyruvate by aspartate + glycerol + octanoate both L-3,4-dihydroxyphenylalanine and tyramine affect neither the rate of gluconeogenesis nor glutathione redox state. In view of: (i) L-3,4-dihydroxyphenylalanine- and tyramine-induced changes in intracellular levels of gluconeogenic intermediates, and (ii) a significant decline of phosphoenolpyruvate carboxykinase activity by 500 microM oxidized glutathione, it is likely that L-3,4-dihydroxyphenylalanine- and tyramine-evoked disturbances in the glutathione redox state might diminish flux through phosphoenolpyruvate carboxykinase and in consequence decrease glucose formation in renal tubules, suggesting a new potential side-action of L-3,4-dihydroxyphenylalanine treatment.
Maleic acid has been shown to be used as a food adulterant in the production of modified starch by the Taiwan Food and Drug Administration. Due to the potential toxicity of maleic acid to the kidneys, this study aimed to develop an analytical method to investigate the pharmacokinetics of maleic acid in rat blood and kidney cortex. Multiple microdialysis probes were simultaneously inserted into the jugular vein and the kidney cortex for sampling after maleic acid administration (10 or 30 mg/kg, i.v., respectively). The pharmacokinetic results demonstrated that maleic acid produced a linear pharmacokinetic phenomenon within the doses of 10 and 30 mg/kg. The area under concentration versus time curve (AUC) of the maleic acid in kidney cortex was 5-fold higher than that in the blood after maleic acid administration (10 and 30 mg/kg, i.v., respectively), indicating that greater accumulation of maleic acid occurred in the rat kidney.
The renal cortex drives renal function. Hypoxia/reoxygenation are primary factors in ischemia-reperfusion (IR) injuries, but renal oxygenation per se is complex and awaits full elucidation. Few mathematical models address this issue: none captures cortical tissue heterogeneity. Using agent-based modeling, we develop the first model of cortical oxygenation at the cell-tissue level (RCM), based on first principles and careful bibliographical analysis. Entirely parameterized with Rat data, RCM is a morphometrically equivalent 2D-slice of cortical tissue, featuring peritubular capillaries (PTC), tubules and interstitium. It implements hemoglobin/O2 binding-release, oxygen diffusion, and consumption, as well as capillary and tubular flows. Inputs are renal blood flow RBF and PO2 feeds; output is average tissue PO2 (tPO2). After verification and sensitivity analysis, RCM was validated at steady-state (tPO2 37.7 ± 2.2 vs. 36.9 ± 6 mmHg) and under transients (ischemic oxygen half-time: 4.5 ± 2.5 vs. 2.3 ± 0.5 s in situ). Simulations confirm that PO2 is largely independent of RBF, except at low values. They suggest that, at least in the proximal tubule, the luminal flow dominantly contributes to oxygen delivery, while the contribution of capillaries increases under partial ischemia. Before addressing IR-induced injuries, upcoming developments include ATP production, adaptation to minutes-hours scale, and segmental and regional specification.
We hypothesized that an interplay between aryl hydrocarbon receptor (AhR) and cysteine-related thiolome at the kidney cortex underlies the mechanisms of (mal)adaptation to chronic intermittent hypoxia (CIH), promoting arterial hypertension (HTN). Using a rat model of CIH-HTN, we investigated the impact of short-term (1 and 7 days), mid-term (14 and 21 days, pre-HTN), and long-term intermittent hypoxia (IH) (up to 60 days, established HTN) on CYP1A1 protein level (a sensitive hallmark of AhR activation) and cysteine-related thiol pools. We found that acute and chronic IH had opposite effects on CYP1A1 and the thiolome. While short-term IH decreased CYP1A1 and increased protein-S-thiolation, long-term IH increased CYP1A1 and free oxidized cysteine. In addition, an in vitro administration of cystine, but not cysteine, to human endothelial cells increased Cyp1a1 expression, supporting cystine as a putative AhR activator. This study supports CYP1A1 as a biomarker of obstructive sleep apnea (OSA) severity and oxidized pools of cysteine as risk indicator of OSA-HTN. This work contributes to a better understanding of the mechanisms underlying the phenotype of OSA-HTN, mimicked by this model, which is in line with precision medicine challenges in OSA.
It has been widely reported that Mori cortex extract (MCE) is used for the treatment of diabetes mellitus in traditional medicine. The present study was designed to investigate its mechanism of action in the treatment of diabetic nephropathy (DN). We assessed whether MCE preventive treatment ameliorates kidney damage in high-fat diet and streptozotocin (STZ)-induced type 2 diabetic rats.
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