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In vitro models of kidneys have limited effectiveness owing to the complex structure and functions of the kidney when compared with other organs. Therefore many renal function evaluations are currently being carried out through animal experiments. In contrast, efforts are being made to apply biomimetic systems, such as organ-on-a-chip, which is based on microfluidic device technology, to serve as an in vitro model for the kidney. These systems aimed to recreate a physiological cultivation environment. This review has provided an overview of organ-on-a-chip research focused on glomeruli and tubules as in vitro models for the kidney and discusses future prospects.

Objective: To investigate the correlation between vibration sensory threshold (VPT) and renal function, including glomerulus and renal tubule, in patients with type 2 diabetes mellitus (T2DM). Methods: A total of 1274 patients with T2DM who were enrolled in the Department of Endocrinology of the First Affiliated Hospital of Fujian Medical University between January 2017 and June 2020 were included. Patients were grouped according to VPT levels and divided into three groups, including the normal VPT group (VPT<15V), the mild-moderate elevated VPT group (VPT15~25V), and the severely elevated VPT group (VPT≥25 V). Linear correlation analysis was used to analyze the correlation between VPT and renal functions, including glomerulus markers urine microalbumin (MA) and urinary immunoglobulin G (U-IgG), and renal tubule marker α1-microglobulin (α1-MG). Chronic kidney disease (CKD) was defined according to Kidney Disease Improving Global Outcomes (KDIGO) criteria. The binary logistic regression of the relation between VPT and CKD, eGFR<60 ml/min, and UACR >30 mg/g were expressed. Results: In the mild-moderate and severely elevated VPT group, injury biomarkers of glomerulus (MA and U-IgG), renal tubule (α1-MG), and the incidence of CKD, eGFR<60 ml/min, and UACR > 30 mg/g were gradually increased compared with the normal VPT group. Furthermore, patients with diabetes and severely elevated VPT had significantly higher levels of MA (β=197.54, p=0.042) and a1-MG (β=11.69, p=0.023) compared to those with normal VPT. Also, patients with mild-moderate elevated VPT demonstrate significantly higher levels of MA (β=229.02, p=0.005). Patients in mildmoderate elevated VPT group (OR=1.463, 95% CI 1.005-2.127; OR=1.816, 95% CI 1.212-2.721) and severely elevated VPT group (OR=1.704, 95% CI 1.113-2.611; OR=2.027, 95% CI 1.248-3.294) are at a higher incidence of CKD and elevated levels of UACR>30mg/g compared to those in the VPT normal group. Moreover, the incidence of positive Upro was notably higher in the severely elevated VPT group (OR=1.738, 95% CI 1.182-2.556). However, this phenomenon was not observed in the incidence of eGFR <60 ml/min. Conclusion: A higher VPT is positively associated with the incidence of CKD in patients with T2DM, particularly with elevated UACR. VPT may serve as a marker for glomerulus and renal tubule injury. [ABSTRACT FROM AUTHOR]

Objective To explore the correlation between markers of tubular injury, 24 h urine protein quantification (24 hUTP) and albumin creatinine ratio (ACR) in patients with diabetic kidney disease (DKD) and explore the relationship between tubular and glomerular injuries to provide guidance for clinical management of DKD. Methods From November 1, 2019 to December 31, 118 proteinuric patients with a definite diagnosis of DKD at outpatient clinic and ward were recruited. And 24 hUTP, ACR, blood creatinine, urinary N-acety1-β-D-glucosaminidase, alpha 1 microglobulin, retinol-binding protein and kidney injury molecule-1 were measured and estimated glomerular filtration rate (eGFR) calculated by the CKD-EPI formula. Linear correlation analysis was utilized for examining the correlation between markers of proximal tubular injury, tubular reabsorption function and 24 hUTP and ACR. Results 24 hUTP at (0.5-3.5) g/24 h, urinary N-acety1-β-D-glucosaminidase, kidney injury molecule-1, alpha 1 microglobulin, retinol-binding protein were correlated linearly with 24 hUTP. The correlation coefficients (adjusted R2) were 0.192, 0.079, 0.054 and 0.040 respectively. Proximal renal tubular injury markers had the highest correlation with 24 hUTP. Urinary N-acety1-β-D-glucosaminidase, kidney injury molecule-1, alpha 1 microglobulin and retinol-binding protein were correlated linearly with ACR. The correlation coefficients (adjusted R2) were 0.367, 0.058, 0.077 and 0.076 respectively with the best correlation between proximal tubular injury markers and ACR. Conclusions In DKD patients, renal tubular injury markers are correlated linearly with 24 hUTP and ACR. Proximal tubular injury markers have the best correlations with 24 hUTP and ACR. Renal tubular injury is correlated closely with the progression of DKD.

Liang Wu,1,2 Martijn H van Heugten,3 Thierry PP van den Bosch,4 Hans Duimel,5 Carmen López-Iglesias,5 Dennis A Hesselink,2 Carla C Baan,2 Karin Boer2 1Department of Nephrology, the First Affiliated Hospital of Shaoyang University, Shaoyang, Hunan, People’s Republic of China; 2Erasmus MC Transplant Institute, University Medical Center Rotterdam, Department of Internal Medicine, Division of Nephrology and Transplantation, Rotterdam, the Netherlands; 3University Medical Center Rotterdam, Department of Internal Medicine, Division of Nephrology and Transplantation, Rotterdam, the Netherlands; 4Department of Pathology, University Medical Center Rotterdam, Rotterdam, the Netherlands; 5The Microscopy CORE Laboratory at the Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, the NetherlandsCorrespondence: Liang Wu, Erasmus MC Transplant Institute, Department of Internal Medicine, University Medical Center Rotterdam Erasmus MC, Room No. Na-514, Doctor Molewaterplein 40, 3015 GD, Rotterdam, the Netherlands, Tel +31 0622145029, Email l.wu.1@erasmusmc.nlPurpose: Kidney transplantation is the optimal treatment for patients with end-stage kidney disease. Donor-specific urinary extracellular vesicles (uEVs) hold potential as biomarkers for assessing allograft status. We aimed to develop a method for identifying donor-specific uEVs based on human leukocyte antigen (HLA) mismatching with the kidney transplant recipients (KTRs).Patients and Methods: Urine and plasma were obtained from HLA-A2+ donors and HLA-A2- KTRs pre-transplant. CD9 (tetraspanin, EV marker) and HLA-A2 double-positive (CD9+ HLA-A2+) EVs were quantified using isolation-free imaging flow cytometry (IFCM). Healthy individuals’ urine was used to investigate CD9+ HLA-class-I+ uEV quantification using IFCM, time-resolved fluoroimmunoassay (TR-FIA), and immunogold staining cryo-electron microscopy (cryo-EM). Culture-derived CD9+ HLA-class-I+ EVs were spiked into the urine to investigate urine matrix effects on uEV HLA detection. Deceased donor kidneys and peritumoral kidney tissue were used for HLA class I detection with histochemistry.Results: The concentrations of CD9+ HLA-A2+ EVs in both donor and recipient urine approached the negative (detergent-treated) control levels for IFCM and were significantly lower than those observed in donor plasma. In parallel, universal HLA class I+ uEVs were similarly undetectable in the urine and uEV isolates compared with plasma, as verified by IFCM, TR-FIA, and cryogenic electron microscopy. Culture supernatant containing HLA class I+ vesicles from B, T, and human proximal tubule cells were spiked into the urine, and these EVs remained stable at 37°C for 8 hours. Immunohistochemistry revealed that HLA class I was predominantly expressed on the basolateral side of renal tubules, with limited expression on their urine/apical side.Conclusion: The detection of donor-specific uEVs is hindered by the limited release of HLA class I+ EVs from the kidney into the urine, primarily due to the polarized HLA class I expression on renal tubules. Identifying donor-specific uEVs requires further advancements in recognizing transplant-specific uEVs and urine-associated markers.Keywords: kidney transplantation, donor-specific biomarker, HLA, extracellular vesicles, human urine, renal tubule

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Abstract Recent studies have suggested that ferroptosis participates in various renal diseases. However, its effect on focal segmental glomerulosclerosis remains unclear. This study analyzed the GSE125779 and GSE121211 datasets to identify the differentially expressed genes (DEGs) in renal tubular samples with and without FSGS. The Cytoscape was used to construct the protein–protein interaction network. Moreover, the ferroptosis-related genes (FRGs) were obtained from the ferroptosis database, while ferroptosis-related DEGs were obtained by intersection with DEGs. The target genes were analyzed using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. The GSE108112 dataset was used to verify the expression of target FRGs. Besides, we built the mRNA-miRNA network regarding FRGs using the NetworkAnalyst database, and circRNAs corresponding to key miRNAs were predicted in the ENCORI database. In this study, 16 ferroptosis-related DEGs were identified between FSGS and healthy subjects, while five co-expressed genes were obtained by three topological algorithms in Cytoscape. These included the most concerned Hub genes JUN, HIF1A, ALB, DUSP1 and ATF3. The KEGG enrichment analysis indicated that FRGs were associated with mitophagy, renal cell carcinoma, and metabolic pathways. Simultaneously, the co-expressed hub genes were analyzed to construct the mRNA-miRNA interaction network and important miRNAs such as hsa-mir-155-5p, hsa-mir-1-3p, and hsa-mir-124-3p were obtained. Finally, 75 drugs targeting 54 important circRNAs and FRGs were predicted. This study identified the Hub FRGs and transcriptomic molecules from FSGS in renal tubules, thus providing novel diagnostic and therapeutic targets for FSGS.

Recent studies have suggested that ferroptosis participates in various renal diseases. However, its effect on focal segmental glomerulosclerosis remains unclear. This study analyzed the GSE125779 and GSE121211 datasets to identify the differentially expressed genes (DEGs) in renal tubular samples with and without FSGS. The Cytoscape was used to construct the protein–protein interaction network. Moreover, the ferroptosis-related genes (FRGs) were obtained from the ferroptosis database, while ferroptosis-related DEGs were obtained by intersection with DEGs. The target genes were analyzed using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. The GSE108112 dataset was used to verify the expression of target FRGs. Besides, we built the mRNA-miRNA network regarding FRGs using the NetworkAnalyst database, and circRNAs corresponding to key miRNAs were predicted in the ENCORI database. In this study, 16 ferroptosis-related DEGs were identified between FSGS and healthy subjects, while five co-expressed genes were obtained by three topological algorithms in Cytoscape. These included the most concerned Hub genes JUN, HIF1A, ALB, DUSP1 and ATF3. The KEGG enrichment analysis indicated that FRGs were associated with mitophagy, renal cell carcinoma, and metabolic pathways. Simultaneously, the co-expressed hub genes were analyzed to construct the mRNA-miRNA interaction network and important miRNAs such as hsa-mir-155-5p, hsa-mir-1-3p, and hsa-mir-124-3p were obtained. Finally, 75 drugs targeting 54 important circRNAs and FRGs were predicted. This study identified the Hub FRGs and transcriptomic molecules from FSGS in renal tubules, thus providing novel diagnostic and therapeutic targets for FSGS. [ABSTRACT FROM AUTHOR]

The current article is devoted to the development of a theoretical model investigating heat transfer analysis of MHD blood flow through renal tubules. For this purpose, we consider the transport of Newtonian fluid inside a non-uniform tube whose lateral surface is kept at constant temperature. The walls of tube are considered to admit the variable permeation and the flow is actuated by an externally applied magnetic field. The solution of the problem is formulated analytically in terms of axial and radial velocities and temperature distribution under the presumption of lubrication approximation in the inertia free flow field. Implication of Darcy’s law for fluid seepage across the tubular membrane results in an ordinary differential equation having variable coefficients for the unknown pressure, which is successfully computed numerically using RK45 routine. Performance of velocity, pressure and temperature distributions has been investigated for various values of the physical parameters involving in the model. Moreover, flow rate behavior, fluid reabsorption and the leakage flux has been analyzed through graphs and tables. The characteristics of heat transfer in the flow field is also evaluated for various values of Brinkman number. A significant discovery reported in the results of present model reveals that the axial flow exhaustion and radial flow reversal are significantly influenced by the tube converging/diverging parameter and the Hartmann number as well. By employing a strong magnetic field, exhaustion and reversal phenomena in the flow field can be restrained up to a certain limit. Moreover, with an increasing wall permeability, there is a significant exhaustion of axial flow in a divergent tube and a prominent assistance takes place in the radial flow reversal for convergent tube. It is hoped that the present model will bear the potential to study flow in renal tubules and in hemodialyzer.

Background: Diabetic nephropathy (DN) is the most common complication of type 2 diabetes mellitus and the main cause of end-stage renal disease worldwide. Diagnostic biomarkers may allow early diagnosis and treatment of DN to reduce the prevalence and delay the development of DN. Kidney biopsy is the gold standard for diagnosing DN; however, its invasive character is its primary limitation. The machine learning approach provides a non-invasive and specific criterion for diagnosing DN, although traditional machine learning algorithms need to be improved to enhance diagnostic performance. Methods: We applied high-throughput RNA sequencing to obtain the genes related to DN tubular tissues and normal tubular tissues of mice. Then machine learning algorithms, random forest, LASSO logistic regression, and principal component analysis were used to identify key genes (CES1G, CYP4A14, NDUFA4, ABCC4, ACE). Then, the genetic algorithm-optimized backpropagation neural network (GA-BPNN) was used to improve the DN diagnostic model. Results: The AUC value of the GA-BPNN model in the training dataset was 0.83, and the AUC value of the model in the validation dataset was 0.81, while the AUC values of the SVM model in the training dataset and external validation dataset were 0.756 and 0.650, respectively. Thus, this GA-BPNN gave better values than the traditional SVM model. This diagnosis model may aim for personalized diagnosis and treatment of patients with DN. Immunohistochemical staining further confirmed that the tissue and cell expression of NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 4-like 2 (NDUFA4L2) in tubular tissue in DN mice were decreased. Conclusion: The GA-BPNN model has better accuracy than the traditional SVM model and may provide an effective tool for diagnosing DN. [ABSTRACT FROM AUTHOR]

Diacylglycerol kinase (DGK) exerts balancing the intracellular level between two-second messengers, diacylglycerol and phosphatidic acid, by its phosphorylation activity. DGK z is often localized in cell nuclei, suggesting its involvement in the regulation of intranuclear activities, including mitosis and apoptosis. The present immunohistochemical study of rat kidneys first revealed no detection levels of DGK z -immunoreactivity in nuclei of most proximal tubule epithelia in contrast to its distinct occurrence in cell nuclei of collecting and distal tubules with the former more dominant. This finding suggests that DGK z is a key factor regulating vulnerability to acute kidney injury in various renal tubules: its low expression represents the high vulnerability of proximal tubule cells, and its distinct expression does the resistance of collecting and distal tubule cells. In addition, this isozyme was more or less localized in nuclei of cells forming glomeruli as well as in endothelial nuclei of peritubular capillaries and other intrarenal blood vessels, and epithelial nuclei of glomerular capsules (Bowman's capsules) and renal calyces, including intrarenal interstitial cells. [ABSTRACT FROM AUTHOR]

Simple Summary: This article presents new data on the histology and ultrastructure of the trunk kidney in two isolated populations of Atlantic salmon, from the Baltic and Barents Seas, covering both the freshwater and the seawater period of their life cycle. We studied juvenile salmon living in freshwater (parr), juvenile salmon running into the sea (smolts), adults feeding in the sea, adults returning to their natal river to spawn, and spawning individuals. According to the results obtained, the ultrastructural changes in the nephron, believed to affect the glomerular filtration rate and the amount of urine produced in salmon kidneys, occurred as early as the smolting stage. Such alterations reflect fundamental changes in the course of pre-adaptation to life in salt water. In the Barents Sea population, the adult salmon caught in the sea had the most pronounced ultrastructural changes, which are characteristic of marine fish. In the salmon that entered the river mouth and stayed in the fresh water for less than a day, structural rearrangements occurred only in the distal tubules of the nephron. The salmon from the Baltic Sea population had less pronounced differences in the morphometric characteristics of the nephron among the studied ontogenetic stages, apparently because of the low salinity in the sampling area. In both studied populations, the activation of cellular immunity was initiated during the parr–smolt transformation. Another distinct immune response was registered in the adults returning to the river for spawning. This article presents data on the mesonephros histology and ultrastructure in the Atlantic salmon from the Baltic Sea and Barents Sea populations, with an emphasis on comparisons between the following ontogenetic stages: parr, smolting, adult life at sea, the adults' return to their natal river to spawn, and spawning. The ultrastructural changes in the renal corpuscle and cells of the proximal tubules of the nephron occurred as early as the smolting stage. Such changes reflect fundamental alterations during the pre-adaptation to life in saltwater. In the Barents Sea population, the adult salmon sampled in the sea had the smallest diameters of the renal corpuscle and proximal and distal tubules, the most narrow urinary space, and the thickest basement membrane. In the group of salmon that entered the mouth of the river and spent less than 24 h in freshwater, the structural rearrangements occurred only in the distal tubules. Better development of the smooth endoplasmic reticulum and a greater abundance of mitochondria in the tubule cells were observed in the adult salmon from the Barents Sea compared to those from the Baltic Sea. Cell-immunity activation was initiated during the parr–smolt transformation. Another pronounced innate-immunity response was registered in the adults returning to the river to spawn. [ABSTRACT FROM AUTHOR]

Central to the maintenance of calcium homeostasis is the regulated reabsorption of calcium along the nephron. To this end, parathyroid hormone (PTH) is released from the parathyroid gland in response to lowered plasma calcium levels. This hormone acts through the PTH 1 receptor along the nephron to increase urinary phosphate excretion and decrease urinary calcium excretion. In the proximal tubule, PTH inhibits phosphate reabsorption by reducing the abundance of sodium phosphate cotransporters in the apical membrane. PTH likely decreases calcium reabsorption from the proximal tubule, by reducing the reabsorption of sodium, an event necessary for the paracellular movement of calcium across this segment. In the thick ascending limb (TAL), PTH increases calcium permeability and may increase the electrical driving force thereby increasing calcium reabsorption in the TAL. Finally, in the distal convolution, PTH acts to increase transcellular calcium reabsorption by increasing the activity and abundance of the apically expressed calcium channel TRPV5. [ABSTRACT FROM AUTHOR]

Objective To investigate the clinicopathological features of recurrent and de novo focal segmental glomerulosclerosis (FSGS) after kidney transplantation. Methods Thirty-four recipients pathologically diagnosed with FSGS by renal allograft biopsy were enrolled in this clinical trial. According to the detection of primary diseases of renal allografts and circulating permeability factors, 34 recipients were divided into the recurrent FSGS group (n=12) and de novo FSGS group (n=22). The differences of clinical indexes and the degree of pathological injury of renal allografts were compared between two groups. Results There was no significant difference in the mesangial hyperplasia score, glomerulosclerosis rate, renal tubular atrophy score, interstitial fibrosis score and podocyte proliferation rate between two groups (all P>0.05). In the recurrent FSGS group, segmental glomerulosclerosis rate of the recipients was 0.10 (0.08, 0.27), lower than 0.19 (0.13, 0.33) in the de novo FSGS group (P<0.05). No significant difference was found in the incidence of antibody-mediated rejection, drug-induced renal tubular injury and BK virus infection between two groups (all P>0.05). The incidence of T cell-mediated rejection in the recurrent FSGS group was 17%, lower than 55% in the de novo FSGS group (P<0.05). Immunohistochemical staining showed that the infiltrating inflammatory cells in the renal allografts were mainly T lymphocytes. The positive rates of C4d deposition in peripheral capillaries between the recurrent and de novo FSGS groups were 33% (4/12) and 32% (7/22), with no significant difference (P>0.05). Immunofluorescence results revealed IgM deposition in the segmental glomerulosclerosis area of renal allografts in most cases. Electron microscopy showed extensive fusion or segmental distribution of podocytes in the glomerulus of renal allografts. Conclusions The degree of renal functional injury and the incidence of T cell-mediated rejection in the recurrent FSGS group are lower than those in the de novo FSGS group. Comprehensive analysis of preoperative and postoperative clinical manifestations, laboratory testing and pathological examination of kidney transplant recipients contribute to early diagnosis and treatment of recurrent and de novo FSGS. [ABSTRACT FROM AUTHOR]

We studied the effect of a preparation containing ultralow doses of formic aldehyde on the course of experimental sepsis caused by intraperitoneal injection of two different strains of Pseudomonas aeruginosa (1623 and 5266) to C57BL/6 male mice. Microscopy and quantitative bacteriological tests in the dynamics of the infectious process demonstrated a positive effect of the drug: 100% survival of animals, preserved histological structure of the studied organs (lungs, liver, kidneys, spleen, and adrenal glands), a sharp decrease in the level of contamination of the blood and organ homogenates during the first hours after infection, and complete absence of bacteria in inoculates on day 7 after infection. These findings suggest the effectiveness of ultralow doses of formic acid aldehyde in the composition of the medicinal product in the treatment of experimental sepsis caused by P. aeruginosa strains 1623 and 5266 in mice. [ABSTRACT FROM AUTHOR]

Hereditary tyrosinemia type Ⅰ (HT1) is a severe autosomal recessive inherited metabolic disease, which can result in severe damage of liver and kidney. Photoacoustic imaging (PAI) uses pulsed laser light to induce ultrasonic signals to facilitate the visualization of lesions that are strongly related to disease progression. In this study, the structural and functional changes of liver and kidney in HT1 was investigated by cross-scale PAI. The results showed that the hepatic lobule and renal tubule were severely damaged during HT1 progression. The hemoglobin content, vessel density, and liver function reserve were decreased. The metabolic half-life of indocyanine green declined from 59.8 s in health to 262.6 s in the advanced stage. Blood oxygen saturation was much lower than that in health. This study highlights the potential of PAI for in vivo evaluation of the liver and kidney lesions in HT1.

Nazareno Carullo,1 Maria Teresa Zicarelli,1 Alessandro Casarella,2 Ramona Nicotera,1 Alberto Castagna,2 Alessandra Urso,1 Pierangela Presta,1 Michele Andreucci,1 Emilio Russo,2 Davide Bolignano,1 Giuseppe Coppolino1 1Renal Unit, Department of Health Sciences, “Magna Graecia” University, Catanzaro, Italy; 2Department of Health Sciences, “Magna Graecia” University, Catanzaro, ItalyCorrespondence: Giuseppe CoppolinoRenal Unit, Department of Health Sciences, “Magna Graecia” University, Viale Europa - Germaneto, Catanzaro, 88100, ItalyTel +39 09613697170Email gcoppolino@unicz.itAbstract: Autosomal dominant polycystic kidney disease (ADPKD) is the most frequent single-gene disorder leading to renal failure. Current therapies are aimed to treat renal and extrarenal complications of ADPKD, but improved knowledge of the pathophysiological mechanisms leading to the generation and growth of cysts has permitted the identification of new drug candidates for clinical trials. Among these, in this review, we will examine above all the role of metformin, hypothesized to be able to activate the AMP-activated protein kinase (AMPK) pathway and potentially modulate some mechanisms implicated in the onset and the growth of the cysts.Keywords: cystogenesis, renal cells, metformin, chronic renal disease, renal tubule

The kidney is an important organ that maintains body fluid homeostasis in seawater and freshwater teleost fishes. Seawater teleosts excrete sulfate and magnesium in small amounts of isotonic urine, and freshwater teleosts excrete water in large amounts of hypo-osmotic urine. The volume, osmolality, and ionic compositions of the urine are regulated mainly by membrane transport proteins expressed in the renal tubular epithelial cells. Gene expression, immunohistochemical, and functional analyses of the fish kidney identified membrane transport proteins involved in the secretion of sulfate and magnesium ions by the proximal tubules and reduction of urine volume by the collecting ducts in seawater teleosts, and excretion of water as hypotonic urine by the distal tubules and collecting ducts in freshwater teleosts. These studies promote an understanding of how the kidney contributes to the seawater and freshwater acclimation of teleosts at the molecular level. [ABSTRACT FROM AUTHOR]

Objective: To observe the effects of nandrolone decanoateon renal tubules and its protection by punicagranatum (pomegranate) in mice. Study Design: Lab based experimental study. Place and Duration of Study: One year in Anatomy department, Army Medical College, Rawalpindi, in association with National Institution of Health, Islamabad. Methodology: Forty healthy BALB/c mice of both sexes with weight range of 2 5-30gms were equally disseminated into four groups, A as control while B, C and D as trial groups. Three trial groups were inoculated Nandrolone Decanoate 1mg per 100gm of body weight, through intramuscular injections in the hind limb, once weekly for eight weeks. Pomegranate nector was administered in animals of trial group C (3ml per kg of body weight) en route oral gavage tube daily, whereas animals in trial group D was administered pomegranate peel extract (200mg per kg body weight) via oral gavage tube daily for eight weeks. Evaluation of the outcomes of trial groups B, C & D was done amongst them and with control group A. Results: In nandrolone decanoate injected experimental group B, tubular necrosis were appreciated in comparison with control group A (p˂ 0.001), and showed statistical improvement when evaluation was done with pomegranate nectar and pomegranate peel extract treated trial groups C (0.001) and D (p=0.001), correspondingly. Conclusion: Punicagranatum in two forms, as nectar and peel extract, has almost identical curative effects on steroid administered renal tubular mutilation.

This article presents data on the mesonephros histology and ultrastructure in the Atlantic salmon from the Baltic Sea and Barents Sea populations, with an emphasis on comparisons between the following ontogenetic stages: parr, smolting, adult life at sea, the adults’ return to their natal river to spawn, and spawning. The ultrastructural changes in the renal corpuscle and cells of the proximal tubules of the nephron occurred as early as the smolting stage. Such changes reflect fundamental alterations during the pre-adaptation to life in saltwater. In the Barents Sea population, the adult salmon sampled in the sea had the smallest diameters of the renal corpuscle and proximal and distal tubules, the most narrow urinary space, and the thickest basement membrane. In the group of salmon that entered the mouth of the river and spent less than 24 h in freshwater, the structural rearrangements occurred only in the distal tubules. Better development of the smooth endoplasmic reticulum and a greater abundance of mitochondria in the tubule cells were observed in the adult salmon from the Barents Sea compared to those from the Baltic Sea. Cell-immunity activation was initiated during the parr–smolt transformation. Another pronounced innate-immunity response was registered in the adults returning to the river to spawn.

Shiga toxin 2 (Stx2) and lipopolysaccharide (LPS) contribute to the development of hemolytic uremic syndrome (HUS). Mouse models of HUS induced by LPS/Stx2 have been used for elucidating HUS pathophysiology and for therapeutic development. However, the underlying molecular mechanisms and detailed injury sites in this model remain unknown. We analyzed mouse kidneys after LPS/Stx2 administration using microarrays. Decreased urinary osmolality and urinary potassium were observed after LPS/Stx2 administration, suggestive of distal nephron disorders. A total of 1,212 and 1,016 differentially expressed genes were identified in microarrays at 6 h and 72 h after LPS/Stx2 administration, respectively, compared with those in controls. Ingenuity pathway analysis revealed activation of TNFR1/2, iNOS, and IL-6 signaling at both time points, and inhibition of pathways associated with lipid metabolism at 72 h only. The strongly downregulated genes in the 72-h group were expressed in the distal nephrons. In particular, genes associated with distal convoluted tubule (DCT) 2/connecting tubule (CNT) and principal cells of the cortical collecting duct (CCD) were downregulated to a greater extent than those associated with DCT1 and intercalated cells. Stx receptor globotriaosylceramide 3 (Gb3) revealed no colocalization with DCT1-specific PVALB and intercalated cell-specific SLC26A4 but did present colocalization with SLC12A3 (present in both DCT1 and DCT2), and AQP2 in principal cells. Gb3 localization tended to coincide with the segment in which the downregulated genes were present. Thus, the LPS/Stx2-induced kidney injury model represents damage to DCT2/CNT and principal cells in the CCD, based on molecular, biological, and physiological findings. [ABSTRACT FROM AUTHOR]

Background The effects of sodium (Na+) intakes on renal handling of potassium (K+) are insufficiently studied. Methods We assessed the effect of Na+ on renal K+ handling in 16 healthy males assigned to three 7-day periods on low salt diet [LSD, 3 g sodium chloride (NaCl)/day], normal salt diet (NSD, 6 g NaCl/day) and high salt diet (HSD, 15 g NaCl/day), with constant K+ intake. Contributions of distal NaCl co-transporter and epithelial Na+ channel in the collecting system on K+ and Na+ handling were assessed at steady state by acute response to 100 mg oral hydrochlorothiazide and with addition of 10 mg of amiloride to hydrochlorothiazide, respectively. Results Diurnal blood pressure slightly increased from 119.30 ± 7.95 mmHg under LSD to 123.00 ± 7.50 mmHg (P = 0.02) under HSD, while estimated glomerular filtration rate increased from 133.20 ± 34.68 mL/min under LSD to 187.00 ± 49.10 under HSD (P = 0.005). The 24-h K+ excretion remained stable on all Na+ intakes (66.28 ± 19.12 mmol/24 h under LSD; 55.91 ± 21.17 mmol/24 h under NSD; and 66.81 ± 20.72 under HSD, P   =   0.9). The hydrochlorothiazide-induced natriuresis was the highest under HSD (30.22 ± 12.53 mmol/h) and the lowest under LSD (15.38 ± 8.94 mmol/h, P   =   0.02). Hydrochlorothiazide increased kaliuresis and amiloride decreased kaliuresis similarly on all three diets. Conclusions Neither spontaneous nor diuretic-induced K+ excretion was influenced by Na+ intake in healthy male subjects. However, the respective contribution of the distal convoluted tubule and the collecting duct to renal Na+ handling was dependent on dietary Na+ intake. [ABSTRACT FROM AUTHOR]

Intracellular calcium is an important regulator of solute transport in renal epithelial cells, and disordered calcium signaling may underlie the pathogenesis of certain kidney diseases. Intravital multiphoton imaging of the kidney in transgenic mice expressing highly sensitive fluorescent reporters allows detailed study of calcium signals within different specialized segments of the renal tubule and how these are integrated with other cellular processes. Moreover, changes in activity can be observed in real time in response to physiological interventions or disease-causing insults. In this chapter, we will provide a detailed protocol for performing this powerful research technique., (© 2025. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Monoclonal gammopathy (MG) causes various nephropathies, which may suffice for cytoreductive therapy even in the absence of diagnostic criteria for multiple myeloma or B-cell non-Hodgkin lymphoma. The aim of this study was to better understand the significance of light chain (LC) restriction or crystals (LC-R/C) in proximal tubules in the spectrum of LC-induced nephropathies. A consecutive cohort of 320 renal specimens with a history of B-cell dyscrasia was characterized. Special attention was paid to immunohistochemical LC restriction in proximal tubules, tubular crystals or constipation, and ultrastructural findings. Complementary cell culture experiments were performed to assess the role of LC concentrations in generating LC restriction. Light chain restriction or crystals in proximal tubules was found in a quarter of analyzed cases (81/316) and was associated with another LC-induced disease in 70.4% (57/81), especially LC cast-nephropathy (cast-NP) and interstitial myeloma infiltration. LC restriction without significant signs of acute tubular injury was observed in 11.1% (9/81). LC-R/C was not associated with inferior renal function compared to the remainder of cases, when cases with accompanying cast-NP were excluded. Besides crystals, cloudy lysosomes were significantly associated with LC-R/C on an ultrastructural level. In summary, LC-R/C is frequent and strongly associated with cast-NP, possibly indicating that a high load of clonal LC is responsible for this phenomenon, supported by the observation that LC restriction can artificially be generated in cell culture. This and the lack of significant tubular injury in a subgroup imply that in part LC-R/C is a tubular trafficking phenomenon rather than an independent disease process.

Autosomal dominant polycystic kidney disease (ADPKD) is the most common congenital kidney disorder, generally caused by mutations in the PKD1 and PKD2 genes, coding for polycystins 1 and 2. Its pathogenesis is accompanied by alterations of the cAMP, mTOR, MAPK/ERK, and JAK/STAT pathways. ADPKD is clinically characterized by the formation of many growing cysts with kidney enlargement and a progressive damage to the parenchyma, up to its complete loss of function, and the onset of end‐stage renal disease (ESRD). The current aim of ADPKD therapy is the inhibition of cyst development and retardation of chronic kidney disease progression. Several drugs have been recently included as potential therapies for ADPKD including metformin, the drug of choice for the treatment of type 2 diabetes mellitus, according to its potential inhibitory effects on cystogenesis. In this review, we summarize preclinical and clinical evidence endorsing or rejecting metformin administration in ADPKD evolution and pathological mechanisms. We explored the biology of APDKD and the role of metformin in slowing down cystogenesis searching PubMed and Clinical Trials to identify relevant data from the database inception to December 2020. From our research analysis, evidence for metformin as emerging cure for ADPKD mainly arise from preclinical studies. In fact, clinical studies are still scanty and stronger evidence is awaited. Its effects are likely mediated by inhibition of the ERK pathway and increase of AMPK levels, which are both linked to ADPKD pathogenesis. [ABSTRACT FROM AUTHOR]

High-salt intake leads to kidney damage and even limits the effectiveness of drugs. However, it is unclear whether excessive intake of salt affects renal tubular energy metabolism and the efficacy of dapagliflozin on renal function in diabetic kidney disease (DKD). In this study, we enrolled 350 DKD patients and examined the correlation between sodium level and renal function, and analyzed influencing factors. The results demonstrated that patients with macroalbuminuria have higher 24 h urinary sodium levels. After establishment of type 2 diabetes mellitus model, the animals received a high-salt diet or normal-salt diet. In the presence of high-salt diet, the renal fibrosis was aggravated with fatty acid metabolism dysregulation. Furthermore, Na+/K+-ATPase expression was up-regulated in the renal tubules of diabetic mice, while the fatty acid metabolism was improved by inhibiting Na+/K+-ATPase of renal tubular epithelial cells. Of note, the administration with dapagliflozin improved renal fibrosis and enhanced fatty acid metabolism. But high salt weakened the above-mentioned renal protective effects of dapagliflozin in DKD. Similar results were recapitulated in vitro after incubating proximal tubular epithelial cells in high-glucose and high-salt medium. In conclusion, our results indicate that high salt can lead to fatty acid metabolism disorders by increasing Na+/K+-ATPase expression in the renal tubules of DKD. High salt intake diminishes the reno-protective effect of dapagliflozin in DKD. [ABSTRACT FROM AUTHOR]

High-salt intake leads to kidney damage and even limits the effectiveness of drugs. However, it is unclear whether excessive intake of salt affects renal tubular energy metabolism and the efficacy of dapagliflozin on renal function in diabetic kidney disease (DKD). In this study, we enrolled 350 DKD patients and examined the correlation between sodium level and renal function, and analyzed influencing factors. The results demonstrated that patients with macroalbuminuria have higher 24 h urinary sodium levels. After establishment of type 2 diabetes mellitus model, the animals received a high-salt diet or normal-salt diet. In the presence of high-salt diet, the renal fibrosis was aggravated with fatty acid metabolism dysregulation. Furthermore, Na+/K+-ATPase expression was up-regulated in the renal tubules of diabetic mice, while the fatty acid metabolism was improved by inhibiting Na+/K+-ATPase of renal tubular epithelial cells. Of note, the administration with dapagliflozin improved renal fibrosis and enhanced fatty acid metabolism. But high salt weakened the above-mentioned renal protective effects of dapagliflozin in DKD. Similar results were recapitulated in vitro after incubating proximal tubular epithelial cells in high-glucose and high-salt medium. In conclusion, our results indicate that high salt can lead to fatty acid metabolism disorders by increasing Na+/K+-ATPase expression in the renal tubules of DKD. High salt intake diminishes the reno-protective effect of dapagliflozin in DKD.

Hyperuricemia (HUA) is a metabolic disorder characterized by elevated serum uric acid (UA), primarily attributed to the hepatic overproduction and renal underexcretion of UA. Despite the elucidation of molecular pathways associated with this underexcretion, the etiology of HUA remains largely unknown. In our study, using by Uox knockout rats, HUA mouse, and cell line models, we discovered that the increased WWC1 levels were associated with decreased renal UA excretion. Additionally, using knockdown and overexpression approaches, we found that WWC1 inhibited UA excretion in renal tubular epithelial cells. Mechanistically, WWC1 activated the Hippo pathway, leading to phosphorylation and subsequent degradation of the downstream transcription factor YAP1, thereby impairing the ABCG2 and OAT3 expression through transcriptional regulation. Consequently, this reduction led to a decrease in UA excretion in renal tubular epithelial cells. In conclusion, our study has elucidated the role of upregulated WWC1 in renal tubular epithelial cells inhibiting the excretion of UA in the kidneys and causing HUA., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

In vitro models of kidneys have limited effectiveness owing to the complex structure and functions of the kidney when compared with other organs. Therefore many renal function evaluations are currently being carried out through animal experiments. In contrast, efforts are being made to apply biomimetic systems, such as organ-on-a-chip, which is based on microfluidic device technology, to serve as an in vitro model for the kidney. These systems aimed to recreate a physiological cultivation environment. This review has provided an overview of organ-on-a-chip research focused on glomeruli and tubules as in vitro models for the kidney and discusses future prospects., Competing Interests: The author declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Author(s).)

Cellular injury caused by stimuli plays an important role in the progression of various diseases including acute and chronic kidney diseases. The dynamic transcriptional regulation responding to stimuli underlies the important mechanism of injury. In this study, we investigated the regulatory elements and their dynamic activities in kidney tubular epithelial cells. We captured the chromatin accessibility and gene expression with ATAC‐seq and RNA sequencing under a variety of extracellular stimuli including H2O2, TGF‐β1, and FG4592 which is an agonist of hypoxia‐inducible factor. Our results revealed both condition‐specific and condition‐shared transcription regulation. Interestingly, the shared regulation program revealed that the key transcription factor HNF1B‐mediated cellular reprogramming leads to a common change among the stimuli. We found the HNF1B regulatory network was significantly disrupted in various kidney diseases. [ABSTRACT FROM AUTHOR]

Objective: To observe the effects of nandrolone decanoateon renal tubules and its protection by punicagranatum (pomegranate) in mice. Study Design: Lab based experimental study. Place and Duration of Study: One year in Anatomy department, Army Medical College, Rawalpindi, in association with National Institution of Health, Islamabad. Methodology: Forty healthy BALB/c mice of both sexes with weight range of 2 5-30gms were equally disseminated into four groups, A as control while B, C and D as trial groups. Three trial groups were inoculated Nandrolone Decanoate 1mg per100 gm of body weight, through intramuscular injections in the hind limb, once weekly for eight weeks. Pomegranate nector was administered in animals of trial group C (3ml per kg of body weight) en route oral gavage tube daily, whereas animals in trial group D was administered pomegranate peel extract (200mg per kg body weight) via oral gavage tube daily for eight weeks. Evaluation of the outcomes of trial groups B, C & D was done amongst them and with control group A. Results: In nandrolone decanoate injected experimental group B, tubular necrosis were appreciated in comparison with control group A (pË, 0.001), and showed statistical improvement when evaluation was done with pomegranate nectar and pomegranate peel extract treated trial groups C (0.001) and D (p=0.001), correspondingly. Conclusion: Punicagranatum in two forms, as nectar and peel extract, has almost identical curative effects on steroid administered renal tubular mutilation. [ABSTRACT FROM AUTHOR]

Renal tubular injury is a critical factor during the early stages of diabetic nephropathy (DN). Proximal tubular epithelial cells, which contain abundant mitochondria essential for intracellular homeostasis, are susceptible to disruptions in the intracellular environment, making them especially vulnerable to diabetic state disorders, which may be attributed to their elevated energy requirements and reliance on aerobic metabolism. It is widely thought that overactivation of the polyol pathway is implicated in DN pathogenesis, and inhibition of aldose reductase (AR), the rate-limiting enzyme in this pathway, represents a promising therapeutic avenue. WJ-39, a novel aldose reductase inhibitor, was investigated in this study for its protective effects on renal tubules in DN and the underlying mechanisms. Our findings revealed that WJ-39 significantly ameliorated the renal tubular morphology in high-fat diet (HFD)/streptozotocin (STZ)-induced DN rats, concurrently inhibiting fibrosis. Notably, WJ-39 safeguarded the structure and function of renal tubular mitochondria by enhancing mitochondrial dynamics. This involved the regulation of mitochondrial fission and fusion proteins and the promotion of PTEN-induced putative kinase 1 (PINK1)/Parkin-mediated mitophagy. Furthermore, WJ-39 demonstrated the inhibition of endogenous apoptosis by mitigating the production of mitochondrial reactive oxygen species (ROS). The protective effects of WJ-39 on mitochondria and apoptosis were countered in high glucose-treated HK-2 cells upon transfection with PINK1 siRNA. Overall, our findings suggest that WJ-39 protects the structural and functional integrity of renal tubules in DN, which may be attributed to its capacity to inhibit aldose reductase activity, activate the PINK1/Parkin signaling pathway, promote mitophagy, and alleviate apoptosis. • Study on pharmacological mechanism of an ARI as a therapeutic drug for DN. • WJ-39 ameliorates renal tubular injury by inhibiting mitochondrial ROS production. • WJ-39 improves mitochondrial dynamics via the PINK1/Parkin pathway. • WJ-39 promotes mitophagy and alleviates apoptosis via PINK1/Parkin signaling in DN. [ABSTRACT FROM AUTHOR]

Primary hyperparathyroidism (PHPT) is a systemic disease that affects all the systems of the body, specifically the bones and the kidneys. Its main action is on calcium homeostasis. It tries to preserve the body's calcium level at the cost of phosphate. The criteria for surgery in asymptomatic PHPT patients revolve around raised serum calcium levels, renal dysfunction or nephrolithiasis, and bone health. It does not take into account the serum phosphate levels. Depending on the serum level, Hypophosphatemia is divided into mild, moderate, and severe categories. In PHPT, several studies have suggested that asymptomatic PHPT patients with moderate hypophosphatemia may warrant surgical intervention. Treatment of hypophosphatemia in PHPT is based upon the degree of hypophosphatemia, and treatment is given according to that oral or intravenous route; after surgical and medical treatment of PHPT, phosphate levels gradually normalized. But even after these considerations, phosphate levels in PHPT are not given much importance. [ABSTRACT FROM AUTHOR]

In this paper, we have discussed the flow of a Newtonian fluid through a slit filled with porous medium and linearly reabsorbing porous walls. The study is motivated by fluid flow in diseased renal tubules in a kidney. Due to diseases, some fibrous material, fatty substances and solid waste particles, etc., may get suspended in tubule channel as well as on the pores of the wall, resulting in the porous filling in the slit and biofouling, respectively. In this study, the absorption at the wall is assumed to follow a linear pattern and the fluid is assumed to be entering the channel at a prescribed initial flow rate. The problem of the two-dimensional fluid flow is formulated using stream function, and inverse solution method is applied to obtain an exact solution of the fourth-order compatibility equation. Some special cases are also deduced from the obtained results and compared with available results from literature. Expressions for various physically relevant quantities like fluid velocities, volume flow rate, fractional reabsorption, leakage flux and pressure distribution are obtained. The results are used to demonstrate how medium porosity and biofouling parameter may affect average pressure differences in the renal tubules of a rat kidney. Finally, the results are presented graphically and effects of changing various parameters on the flow are analysed. We have also deduced some special cases when the wall reabsorption is uniform, and when there is no medium porosity. We have shown these special cases match with the already present results in the literature. [ABSTRACT FROM AUTHOR]

The flow of the Ellis fluid in the renal tubule is investigated in this paper. The fluid absorption at the wall is influenced by the pressure gradient across the wall and by the permeability of the wall. The governing equations are considerably simplified if the tubule radius is assumed to be much smaller than its length. Important quantities of interest are computed numerically. The results are compared with available data and are found to be in good agreement. [ABSTRACT FROM AUTHOR]

AimAcute hyperglycemia is closely related to kidney injury. Oxidative stress activation and notable mitochondria damages were found under acute hyperglycemia treatment in our previous work. In the present study, we explored the dose-effect relationship and the pivotal role of mitophagy in acute hyperglycemia induced tubular injuries.MethodsForty non-diabetic SD rats were randomly divided and treated with different concentrations of hyperglycemia respectively during the 6-h clamp experiment. Renal morphological and functional alterations were detected. Rat renal tubular epithelial cells were treated with different concentrations of glucose for 6 h. Markers and the regulation pathway of mitophagy were analyzed.ResultsSignificant tubular injuries but not glomeruli were observed under both light and electron microscope after acute hyperglycemia treatment, which manifested as enlargement of tubular epithelial cells, disarrangement of epithelial cell labyrinths and swelling of mitochondria. Urinary microalbumin, β2-MG, CysC, NAG, GAL, and NGAL were increased significantly with the increase of blood glucose (P < 0.05). ROS was activated, mitochondrial membrane potential and LC3-II/LC3-I ratio were decreased but P62 and BNIP3L/Nix were increased in hyperglycemia groups (P < 0.05), which were reversed by AMPK activation or mTOR inhibition.ConclusionAcute hyperglycemia causes obvious tubular morphological and functional injuries in a dose-dependent manner. Acute hyperglycemia could inhibit mitophagy through AMPK/mTOR pathway, which would aggravate mitochondria damage and renal tubular impairment.

Objective: To investigate the correlation between vibration sensory threshold (VPT) and renal function, including glomerulus and renal tubule, in patients with type 2 diabetes mellitus (T2DM)., Methods: A total of 1274 patients with T2DM who were enrolled in the Department of Endocrinology of the First Affiliated Hospital of Fujian Medical University between January 2017 and June 2020 were included. Patients were grouped according to VPT levels and divided into three groups, including the normal VPT group (VPT<15V), the mild-moderate elevated VPT group (VPT15~25V), and the severely elevated VPT group (VPT≥25 V). Linear correlation analysis was used to analyze the correlation between VPT and renal functions, including glomerulus markers urine microalbumin (MA) and urinary immunoglobulin G (U-IgG), and renal tubule marker α1-microglobulin (α1-MG). Chronic kidney disease (CKD) was defined according to Kidney Disease Improving Global Outcomes (KDIGO) criteria. The binary logistic regression of the relation between VPT and CKD, eGFR<60 ml/min, and UACR >30 mg/g were expressed., Results: In the mild-moderate and severely elevated VPT group, injury biomarkers of glomerulus (MA and U-IgG), renal tubule (α1-MG), and the incidence of CKD, eGFR<60 ml/min, and UACR > 30 mg/g were gradually increased compared with the normal VPT group. Furthermore, patients with diabetes and severely elevated VPT had significantly higher levels of MA (β=197.54, p=0.042) and α1-MG (β=11.69, p=0.023) compared to those with normal VPT. Also, patients with mild-moderate elevated VPT demonstrate significantly higher levels of MA (β=229.02, p=0.005). Patients in mild-moderate elevated VPT group (OR=1.463, 95% CI 1.005-2.127; OR=1.816, 95% CI 1.212-2.721) and severely elevated VPT group (OR=1.704, 95% CI 1.113-2.611; OR=2.027, 95% CI 1.248-3.294) are at a higher incidence of CKD and elevated levels of UACR>30mg/g compared to those in the VPT normal group. Moreover, the incidence of positive Upro was notably higher in the severely elevated VPT group (OR=1.738, 95% CI 1.182-2.556). However, this phenomenon was not observed in the incidence of eGFR <60 ml/min., Conclusion: A higher VPT is positively associated with the incidence of CKD in patients with T2DM, particularly with elevated UACR. VPT may serve as a marker for glomerulus and renal tubule injury., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Zhang, Zheng, Li, Shen, Huang, Zhao and Yan.)

'On-a-chip' technology advances the development of physiologically relevant organ-mimicking architecture by integrating human cells into three-dimensional microfluidic devices. This method also establishes discrete functional units, faciliting focused research on specific organ components. In this study, we detail the development and assessment of a convoluted renal proximal tubule-on-a-chip (PT-on-a-chip). This platform involves co-culturing Renal Proximal Tubule Epithelial Cells (RPTEC) and Human Umbilical Vein Endothelial Cells (HUVEC) within a polydimethylsiloxane microfluidic device, crafted through a combination of 3D printing and molding techniques. Our PT-on-a-chip significantly reduced high glucose level, exhibited albumin uptake, and simulated tubulopathy induced by amphotericin B. Remarkably, the RPTEC:HUVEC co-culture exhibited efficient cell adhesion within 30 min on microchannels functionalized with plasma, 3-aminopropyltriethoxysilane, and type-I collagen. This approach significantly reduced the required incubation time for medium perfusion. In comparison, alternative methods such as plasma and plasma plus polyvinyl alcohol were only effective in promoting cell attachment to flat surfaces. The PT-on-a-chip holds great promise as a valuable tool for assessing the nephrotoxic potential of new drug candidates, enhancing our understanding of drug interactions with co-cultured renal cells, and reducing the need for animal experimentation, promoting the safe and ethical development of new pharmaceuticals., (© 2024 IOP Publishing Ltd.)

The chemical constituents of Draconis Sanguis were preliminarily studied by macroporous resin, silica gel, dextran gel, and high-performance liquid chromatography. One retro-dihydrochalcone, four flavonoids, and one stilbene were isolated. Their chemical structures were identified as 4-hydroxy-2,6-dimethoxy-3-methyldihydrochalcone(1), 4'-hydroxy-5,7-dimethoxy-8-methylflavan(2), 7-hydroxy-4',5-dimethoxyflavan(3),(2S)-7-hydroxy-5-methoxy-6-methylflavan(4),(2S)-7-hydroxy-5-methoxyflavan(5), and pterostilbene(6) by modern spectroscopy, physicochemical properties, and literature comparison. Compound 1 was a new compound. Compounds 2 and 6 were first found in the Arecaceae family. Compound 5 had the potential to prevent and treat diabetic kidney disease.

Aim: Acute hyperglycemia is closely related to kidney injury. Oxidative stress activation and notable mitochondria damages were found under acute hyperglycemia treatment in our previous work. In the present study, we explored the dose-effect relationship and the pivotal role of mitophagy in acute hyperglycemia induced tubular injuries. Methods: Forty non-diabetic SD rats were randomly divided and treated with different concentrations of hyperglycemia respectively during the 6-h clamp experiment. Renal morphological and functional alterations were detected. Rat renal tubular epithelial cells were treated with different concentrations of glucose for 6 h. Markers and the regulation pathway of mitophagy were analyzed. Results: Significant tubular injuries but not glomeruli were observed under both light and electron microscope after acute hyperglycemia treatment, which manifested as enlargement of tubular epithelial cells, disarrangement of epithelial cell labyrinths and swelling of mitochondria. Urinary microalbumin, β2-MG, CysC, NAG, GAL, and NGAL were increased significantly with the increase of blood glucose (P < 0.05). ROS was activated, mitochondrial membrane potential and LC3-II/LC3-I ratio were decreased but P62 and BNIP3L/Nix were increased in hyperglycemia groups (P < 0.05), which were reversed by AMPK activation or mTOR inhibition. Conclusion: Acute hyperglycemia causes obvious tubular morphological and functional injuries in a dose-dependent manner. Acute hyperglycemia could inhibit mitophagy through AMPK/mTOR pathway, which would aggravate mitochondria damage and renal tubular impairment. [ABSTRACT FROM AUTHOR]

Kidneys play a central role in regulation of potassium homeostasis and maintenance of plasma K+ levels within a narrow physiological range. With-no-lysine (WNK) kinases, specifically WNK1 and WNK4, have been recognized to regulate K+ balance, in part, by orchestrating maxi K+ channel (BK)-dependent K+ secretion in the aldosterone-sensitive distal nephron (ASDN), which includes the connecting tubule and collecting duct. We recently demonstrated that the Ca2+-permeable TRPV4 channel is essential for BK activation in the ASDN. Furthermore, high K+ diet increases TRPV4 activity and expression largely in an aldosterone-dependent manner. In the current study, we aimed to test whether WNK kinases contribute to regulation of TRPV4 activity and its stimulation by aldosterone. Systemic inhibition of WNK with WNK463 (1 mg/kgBW for 3 days) markedly decreased TRPV4-dependent Ca2+ influx in freshly isolated split-opened collecting ducts. Aldosterone greatly increased TRPV4 activity and expression in cultured mpkCCDc14 cells and this effect was abolished in the presence of WNK463. Selective inhibition of WNK1 with WNK-in-11 (400 nM, 24 h) recapitulated the effects of WNK463 on TRPV4-dependent Ca2+ influx. Interestingly, WNK-in-11 did not interfere with up-regulation of TRPV4 expression by aldosterone, but prevented translocation of the channel to the apical plasma membrane. Furthermore, co-expression of TRPV4 and WNK1 into Chinese hamster ovary (CHO) cells increased the macroscopic TRPV4-dependent cation currents. In contrast, over-expression of TRPV4 with a dominant negative WNK1 variant (K233M) decreased the whole-cell currents, suggesting both stimulatory and permissive roles of WNK1 in regulation of TRPV4 activity. Overall, we show that WNK1 is essential for setting functional TRPV4 expression in the ASDN at the baseline and in response to aldosterone. We propose that this new mechanism contributes to regulation of K+ secretion and, by extension, urinary K+ levels to maintain systemic potassium homeostasis.

Background/Aims: To explore the protective effect of curcumin on renal ischemia-reperfusion injury (RIRI) in rats, and its influence on nephridial tissue’s NO and cGMP levels as well as downstream signaling pathway, to elucidate the possible mechanism of curcumin on RIRI. Methods: 36 Sprague Dawley rats (SD rats) were randomly divided into Sham group, Model group, curcumin (CUR +) Model group, 12 rats per group. They were all given RIRI model preparation by unilateral artery occlusion method. All groups’ β2-MG in urine in 24h, serum Cr and BUN were compared, and UAER were calculated. Nitric oxide synthase (NOS), cGMP-dependent protein kinase (PKG), Caspase-3 expression were all determined by western blot. Nitric oxide (NO), NOS and cGMP levels were also examined by using ELISA. All groups’ nephridial histomorphology and kidney tubules score were evaluated and compared. Results: β2-MG and UAER in urine, serum Cr and BUN, in renal tissue were all elevated in Model of RIRI, indicating the success of animal model of RIRI establishment, and above index in CUR + Model group were all lower than those in Model group. Furthermore, iNOS, NO, cGMP, PKG and Caspase-3 in renal tissue were all increased in Model of RIRI, indicating the NO signaling pathway was activated, which is one of the pathogenesis of RIRI, and above index in CUR + Model group were all lower than those in Model group, suggesting that inactivation of iNOS/NO/cGMP/PKG signaling pathway is one of the reasons that explain the protective effect of curcumin in RIRI. Conclusion: The activation of iNOS/NO/cGMP/PKG signaling pathway and the consequent promoted apoptosis of renal tubules are significantly involved in the pathogenesis of development of RIRI, and curcumin treatment could protect renal tubules against RIRI, at least partially, by suppressing the activated iNOS/NO/cGMP/PKG signaling pathway.