Acute Kidney Injury ; etiology ; Betacoronavirus ; Coronavirus Infections ; complications ; Humans ; Kidney ; enzymology ; Pandemics ; Peptidyl-Dipeptidase A ; physiology ; Pneumonia, Viral ; complications ; Sequence Analysis, RNA ; methods ; Serine Endopeptidases ; physiology ; Single-Cell Analysis ; methods

BACKGROUND: High fluoride levels in drinking water in relation to the prevalence of chronic kidney disease of unknown etiology (CKDu) in Sri Lanka were investigated using rats as an experimental model. METHOD: The effects of fluoride after oral administration of Sodium fluoride (NaF) at levels of 0, 0.5, 5 and 20 ppm F were evaluated in adult male Wistar rats. Thirty-six rats were randomly divided into 4 groups (n = 9), namely, control, test I, II, and III. Control group was given daily 1 ml/rat of distilled water and test groups I, II, and III were treated 1 ml/rat of NaF doses of 0.5, 5, and 20 ppm, respectively, by using a stomach tube. Three rats from the control group and each experimental group were sacrificed after 15, 30, and 60 days following treatment. Serological and histopathological investigations were carried out using blood, kidney, and liver. RESULTS: No significant differences were observed in body weight gain and relative organ weights of the liver and kidney in fluoride-treated groups compared to control group. After 60 days of fluoride administration, group I showed a mild portal inflammation with lytic necrosis while multiple areas of focal necrosis and various degrees of portal inflammation were observed in groups II and III. This was further confirmed by increased serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) activities. As compared with control and other treated groups, group III showed a significantly higher serum AST activity (p < 0.05) and ALT activity (p < 0.05) after 60 days and ALP activity with a significant difference (p < 0.05) after 15, 30, and 60 days. The renal histological analysis showed normal histological features in all groups with the elevated serum creatinine levels in group III compared to those in the groups I and II (p < 0.05) after 60 days. Significantly elevated serum fluoride levels were observed in group II of 30 and 60 days and group III after 15, 30, and 60 days with respective to control groups (p < 0.05). CONCLUSION Taken together, these findings indicate that there can be some alterations in liver enzyme activities at early stages of fluoride intoxication followed by renal damage.
Animals ; Dose-Response Relationship, Drug ; Fluorides ; adverse effects ; Humans ; Kidney ; drug effects ; enzymology ; pathology ; Liver ; drug effects ; enzymology ; pathology ; Male ; Organ Size ; drug effects ; Random Allocation ; Rats ; Rats, Wistar ; Renal Insufficiency, Chronic ; etiology

Renal anemia, mainly caused by the deficiencies of erythropoietin (EPO) and iron metabolism disorder, is one of the most common complications of chronic kidney disease. Hypoxia-inducible factor (HIF) is a class of transcription factors responsible for maintaining homeostasis during oxygen deprivation. In normoxia, HIF is degraded by prolyl hydroxylase (PHD). While under hypoxic conditions, the hydroxylation activity of PHD is inhibited, and the cellular concentration of HIF is elevated, resulting in an increase in endogenous EPO production and iron absorption. Therefore, this regulating pathway, also termed as the HIF-PHD axis, has become a promising therapeutic target of treating renal anemia. Several innovative drugs acting as selective HIF-PHD inhibitors have been successfully developed in the past years, and some of them are undergoing clinical trials. In this review, we will introduce the definition and regulatory mechanism of HIF-PHD axis, as well as current insights into its physiologic and therapeutic role in renal anemia.
Anemia ; enzymology ; pathology ; Humans ; Hypoxia ; pathology ; Hypoxia-Inducible Factor 1 ; metabolism ; Kidney Diseases ; enzymology ; pathology ; Oxygen ; Prolyl Hydroxylases ; metabolism

OBJECTIVETo investigate the expression of 17 beta-hydroxysteroid dehydrogenase type 1 (17β-HSD1) in the kidney of rats and explore the capacity of the kidney for synthesizing sex hormones.

METHODSThe expressions of 17-HSD1 and sex hormones were detected by Western blotting and radioimmunoassay in rat renal cells in primary cultured for 24 and 48 h in the presence or absence of follicle-stimulating hormone (FSH) and luteinizing hormone (LH).

RESULTSAfter cell culture for 24 h, the primary rat renal cells expressed a low level of 17β-HSD1 (0.1843±0.076), which increased to 1.6651±0.044 (P<0.01) in response to co-stimulation by FSH and LH. Low levels of estradiol, progesterone and testosterone were also detected in rat renal cells (3.30±3.78, 62.60±12.33, and 22.12±3.36, respectively), and co-stimulation of FSH and LH significantly increased their levels to 8.50±2.64, 117.80±9.79, and 45.04±4.39, respectively (P<0.05). The levels of these hormones showed no significant differences between cells cultured for 24 h and 48 h (P>0.05).

CONCLUSIONThe rat renal cells express 17β-HSD1 and are capable of stably secreting sex hormones in response to co-stimulation with FSH and LH, suggesting the capacity of the rat kidneys for synthesizing sex hormones. These findings enrich the understanding of the endocrine function of the kidney.

17-Hydroxysteroid Dehydrogenases ; metabolism ; Animals ; Cells, Cultured ; Estradiol ; biosynthesis ; Follicle Stimulating Hormone ; pharmacology ; Kidney ; enzymology ; Luteinizing Hormone ; pharmacology ; Progesterone ; biosynthesis ; Rats ; Testosterone ; biosynthesis

The present study aimed at determining whether berberine can enhance the antidiabetic effects and alleviate the adverse effects of canagliflozin in diabetes mellitus. Streptozotocin-induced diabetic mice were introduced, and the combined effects of berberine and canagliflozin on glucose metabolism and kidney functions were investigated. Our results showed that berberine combined with canagliflozin (BC) increased reduction of fasting and postprandial blood glucose, diet, and water intake compared with berberine or canagliflozin alone. Interestingly, BC showed greater decrease in blood urea nitrogen and creatinine levels and lower total urine glucose excretion than canagliflozin alone. In addition, BC showed increased phosphorylated 5' AMP-activated protein kinase (pAMPK) expression and decreased tumor necrosis factor alpha (TNFα) levels in kidneys, compared with berberine or canagliflozin alone. These results indicated that BC was a stronger antidiabetic than berberine or canagliflozin alone with less negative side effects on the kidneys in the diabetic mice. The antidiabetic effect was likely to be mediated by synergically promoting the expression of pAMPK and reducing the expression of TNFα in kidneys. The present study represented the first report that canagliflozin combined with berberine was a promising treatment for diabetes mellitus. The exact underlying mechanisms of action should be investigated in future studies.
AMP-Activated Protein Kinases ; metabolism ; Animals ; Berberine ; administration & dosage ; Blood Glucose ; metabolism ; Canagliflozin ; administration & dosage ; adverse effects ; Diabetes Mellitus, Experimental ; drug therapy ; metabolism ; Drug Therapy, Combination ; Drugs, Chinese Herbal ; administration & dosage ; Humans ; Hypoglycemic Agents ; administration & dosage ; Insulin ; metabolism ; Kidney ; drug effects ; enzymology ; metabolism ; Male ; Mice ; Streptozocin

Glomerular hypertrophy is the main pathological characteristic in the early stage of diabetic nephropathy (DN), and its regulatory mechanism is closely related to mammalian target of rapamycin (mTOR) signaling pathway activity. mTOR includes mTOR complex 1 (mTORC1) and mTOR complex 2(mTORC2), in which, the upstream pathway of mTORC1 is phosphatidylinositol-3-kinase (PI3K)/serine-threonine kinase(Akt)/adenosine monophosphate activated protein kinase(AMPK), and the representative signaling molecules in the downstream pathway of mTORC1 are 4E-binding proteins(4EBP) and phosphoprotein 70 S6Kinase(p70S6K). Some Chinese herbal extracts could improve cell proliferation via intervening the expressions of the key molecules in the upstream or downstream of PIK/Akt/mTOR signaling pathway in vivo. As for glomerular mesangial cells(MC) and podocyte, mTOR plays an important role in regulating glomerular inherent cells, including adjusting cell cycle, energy metabolism and matrix protein synthesis. Rapamycin, the inhibitor of mTOR, could suppress glomerular inherent cell hypertrophy, cell proliferation, glomerular basement membrane (GBM) thickening and mesangial matrix deposition in model rats with DN. Some Chinese herbal extracts could alleviate glomerular lesions by intervening mTOR signaling pathway activity in renal tissue of DN animal models or in renal inherent cells in vivo and in vitro.
Animals ; Diabetic Nephropathies ; drug therapy ; enzymology ; genetics ; pathology ; Drugs, Chinese Herbal ; administration & dosage ; Humans ; Hypertrophy ; drug therapy ; enzymology ; genetics ; pathology ; Kidney Glomerulus ; drug effects ; metabolism ; pathology ; Signal Transduction ; drug effects ; TOR Serine-Threonine Kinases ; genetics ; metabolism

To assess the neurotoxic effects and redox responses of Aroclor 1254 (A1254) on perinatally exposed rat offspring, A1254 was administered by gavage from gestational day (GD) 6 to postnatal day (PND) 21. Neurobehavioral development, antioxidant enzyme activities, lipid peroxidation (LPO), nitric oxide (NO), and NO synthase (NOS) levels were analyzed in the offspring. Neurobehavioral development analysis revealed delayed appearance of the righting reflex, negative geotaxis, and cliff drop test responses in A1254 exposed group. Developmental A1254 exposure also caused oxidative stress in the brain of PND 22 offspring via reductions in the activity of SOD and GSH-Px, and by promoting a rise in the levels of NO and NOS.
Aging ; metabolism ; Animals ; Cerebral Cortex ; drug effects ; enzymology ; metabolism ; Chlorodiphenyl (54% Chlorine) ; toxicity ; Female ; Glutathione Peroxidase ; metabolism ; Kidney ; drug effects ; enzymology ; metabolism ; Lipid Peroxidation ; drug effects ; Liver ; drug effects ; enzymology ; metabolism ; Mice ; Nervous System ; drug effects ; growth & development ; metabolism ; physiopathology ; Nervous System Diseases ; chemically induced ; Nitric Oxide ; metabolism ; Nitric Oxide Synthase ; metabolism ; Oxidative Stress ; drug effects ; Pregnancy ; Prenatal Exposure Delayed Effects ; chemically induced ; Random Allocation ; Rats ; Superoxide Dismutase ; metabolism

BACKGROUNDSrc homology 2 domain-containing protein tyrosine phosphatase-2 (SHP-2) is a kind of intracellular protein tyrosine phosphatase. Studies have revealed its roles in various disease, however, whether SHP-2 involves in renal fibrosis remains unclear. The aim of this study was to explore the roles of myeloid cells SHP-2 in renal interstitial fibrosis.

METHODSMyeloid cells SHP-2 gene was conditionally knocked-out (CKO) in mice using loxP-Cre system, and renal interstitial fibrosis was induced by unilateral ureter obstruction (UUO). The total collagen deposition in the renal interstitium was assessed using picrosirius red stain. F4/80 immunostaing was used to evaluate macrophage infiltration in renal tubular interstitium. Quantitative real-time polymerase chain reaction and enzyme linked immunosorbent assay were used to analyze the production of cytokines in the kidney. Transferase-mediated dUTP nick-end labeling stain was used to assess the apoptotic renal tubular epithelial cells.

RESULTSSrc homology 2 domain-containing protein tyrosine phosphatase-2 gene CKO in myeloid cells significantly reduced collagen deposition in the renal interstitium after UUO. Macrophage infiltration was evidently decreased in renal tubular interstitium of SHP-2 CKO mice. Meanwhile, the production of pro-inflammatory cytokines was significantly suppressed in SHP-2 CKO mice. However, no significant difference was observed in the number of apoptotic renal tubular epithelial cells between wild-type and SHP-2 CKO mice.

CONCLUSIONSOur observations suggested that SHP-2 in myeloid cells plays a pivotal role in the pathogenesis of renal fibrosis, and that silencing of SHP-2 gene in myeloid cells may protect renal from inflammatory damage and prevent renal fibrosis after renal injury.

Animals ; Enzyme-Linked Immunosorbent Assay ; Female ; Fibrosis ; enzymology ; pathology ; Immunohistochemistry ; Kidney Diseases ; enzymology ; pathology ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Myeloid Cells ; metabolism ; Protein Tyrosine Phosphatase, Non-Receptor Type 11 ; genetics ; metabolism ; Ureteral Obstruction ; enzymology ; pathology

BACKGROUND: To explore the role of protein phosphatase 2A (PP2A) in renal interstitial fibrosis by using rat model of unilateral ureteral obstructive (UUO) or cell model of human kidney proximal tubular epithelial (HK)-2 cells treated with transforming growth factor-β1 (TGF-β1).
 METHODS: 1) A total of 15 Sprague-Dawley rats were randomly divided into a sham group, a UUO group and an okadaic acid (OA) treated group (OA group) (n=5 in each group). The OA 
[30 μg/(kg·d)], diluted with 1.8% alcohol, was given to the rats in the OA group through gastric tube after at 72 h after the surgery, while the equal volume of 1.8% alcohol was given to the rats in the sham group and the UUO group. After sacrificing rats, the blood and kidney were collected to detect the renal function and the expression of PP2Ac, fibronectin (FN), collagen-I (Col-I), E-cadherin (E-cad) and α-smooth muscle actin (α-SMA) by immunohistochemistry, Western blot and RT-PCR, respectively; 2) The likely concentration of OA was determined by Trypan blue dye exclusive assay and methylthiazolyldiphenyl-tetrazolium bromide (MTT) assay. The HK-2 cells were incubated with serum-free Dulbecco's modified eagle medium (DMEM) for 24 h; then they were divided into a control group, a TGF-β1 group (treated with 5 ng/mL TGF-β1 for 24 h) and a TGF-β1+OA group (treated with 5 ng/mL TGF-β1 and 40 nmol/L OA for 24 h). The HK-2 cells were collected and the expression of PP2Ac, FN, Col-I, E-cad and α-SMA were detected by Western blot.
 RESULTS: 1) Compared with the sham group, the BUN and Scr in the UUO group increased (both P<0.05); compared with the UUO group, the BUN and Scr in the OA group decreased (both P<0.05); the expression of PP2Ac, FN, Col-I and α-SMA was up-regulated while the expression of E-cad was down-regulated in the UUO group compared with those in the sham group (all P<0.05). The expression of PP2Ac, FN, Col-I and α-SMA was down-regulated while the expressions of E-cad was up-regulated in the OA group compared with those in the UUO group (all P<0.05); 2) The likely concentration of OA was 40 nmol/L. Western blot showed that the expression of PP2Ac, FN, Col-I and α-SMA was up-regulated while the expressions of E-cad was down-regulated in the TGF-β1 group compared with those in the control group (all P<0.05); the expression of PP2Ac, FN, Col-I and α-SMA were down-regulated while the expression of E-cad was up-regulated in the TGF-β1+OA group compared with those in the TGF-β1 group (all P<0.05).
 CONCLUSIONS PP2A might be able to promote the renal interstitial fibrosis.
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Actins ; metabolism ; Animals ; Cadherins ; metabolism ; Cell Line ; Collagen Type I ; metabolism ; Drugs, Chinese Herbal ; Fibronectins ; metabolism ; Fibrosis ; Humans ; Kidney ; metabolism ; pathology ; Kidney Diseases ; enzymology ; Protein Phosphatase 2 ; metabolism ; Rats ; Rats, Sprague-Dawley ; Transforming Growth Factor beta1 ; pharmacology

BACKGROUNDOenanthe javanica is an aquatic perennial herb originated from East Asia. Nowadays, the effects of Oenanthe javanica have been proven in various disease models. Studies regarding the antioxidant effect of Oenanthe javanica in the kidney are still unclear.

METHODSThis study was therefore performed to investigate the effect of the Oenanthe javanica extract (OJE) in the rat kidney using immunohistochemistry for antioxidant enzymes, copper, zinc-superoxide dismutase (SOD1), manganese superoxide dismutase (SOD2), catalase (CAT) and glutathione peroxidase (GPx). Sprague-Dawley rats were randomly assigned to three groups: (1) normal diet fed-group (normal-group), (2) diet containing ascorbic acid (AA)-fed group (AA-group) as a positive control, (3) diet containing OJE-fed group (OJE-group). AA and OJE were supplied during 28 days.

RESULTSThe side-effects were not observed in all the groups. Immunoreactivities of SOD1, SOD2, CAT and GPx were easily detected in the distal tubules of the kidney, and their immunoreactivities in the AA-and OJE-groups were increased to about 1.4-1.5 times and 2 times, respectively, compared with those in the normal-group.

CONCLUSIONOJE significantly increased expressions of SOD1 & 2, CAT and GPx immunoreactivities in the distal tubules of the rat kidney, and this finding suggests that significant enhancements of endogenous enzymatic antioxidants by OJE treatment may be a legitimate strategy for decreasing oxidative stresses in the kidney.

Animals ; Antioxidants ; metabolism ; Catalase ; metabolism ; Glutathione Peroxidase ; metabolism ; Kidney ; drug effects ; enzymology ; metabolism ; Male ; Oenanthe ; chemistry ; Oxidative Stress ; drug effects ; Plant Extracts ; chemistry ; pharmacology ; Rats ; Rats, Sprague-Dawley ; Superoxide Dismutase ; metabolism