Primary polydipsia, but not accumulated ceramide, causes lethal renal damage in saposin D-deficient mice

2012 ◽  
Vol 303 (7) ◽  
pp. F1049-F1059 ◽  
Author(s):  
Harumi Hisaki ◽  
Junko Matsuda ◽  
Keiko Tadano-Aritomi ◽  
Shunya Uchida ◽  
Hiroko Okinaga ◽  
...  

Saposin D-deficient (Sap-D−/−) mice develop polydipsia/polyuria and die prematurely due to renal failure with robust hydronephrosis. Such symptoms emerged when they were around 3 mo of age. To investigate the pathogenesis of their water mishandling, we attempted to limit water supply and followed sequential changes of physiological and biochemical parameters. We also analyzed renal histological changes at several time points. At 3 mo old just before water restriction challenge was started, their baseline arginine vasopressin level was comparable to the wild-type (WT) level. Twenty-four-hour water deprivation and desamino d-arginine vasopressin administration improved polydipsia and polyuria to certain degrees. However, creatinine concentrations in Sap-D−/− mice were significantly higher than those in WT mice, suggesting that some renal impairment already emerged in the affected mice at this age. Renal histological analyses revealed that renal tubules and collecting ducts were expanded after 3 mo old. After 6 mo old, vacuolar formation was observed, many inflammatory cells migrated around the ducts, and epithelial monolayer cells of tubular origin were replaced by plentiful cysts of various sizes. At 10∼12 mo old, severe cystic deformity appeared. On the other hand, 8-mo-long water restriction started at 4 mo old dramatically improved tubular damage and restored once-dampened amount of tubular aquaporin2 protein to the WT level. Furthermore, 10-mo-long water restriction ameliorated their renal function. Remarkably, by continuing water restriction thereafter, overall survival period became comparable with that of the WT. Together, polyuria, devastating renal tubular lesions, and renal failure were ameliorated by the mere 10-mo-long water restriction, which would trigger lethal dehydration if the disease were to be caused by any processes other than primary polydipsia. Our study demonstrates that long-term water restriction surely improved renal histopathological changes leading to prevention of premature death in Sap-D−/− mice.

2008 ◽  
Vol 294 (2) ◽  
pp. F326-F335 ◽  
Author(s):  
Hiroyuki Ohnishi ◽  
Shinya Mizuno ◽  
Toshikazu Nakamura

During the progression of acute renal failure (ARF), the renal tubular S3 segment is sensitive to ischemic stresses. For reversing tubular damage, resident tubular cells proliferate, and bone marrow-derived cells (BMDC) can be engrafted into injured tubules. However, how resident epithelium or BMDC are involved in tubular repair remains unknown. Using a mouse model of ARF, we examined whether hepatocyte growth factor (HGF) regulates a balance of resident cell proliferation and BMDC recruitment. Within 48 h post-renal ischemia, tubular destruction became evident, followed by two-waved regenerative events: 1) tubular cell proliferation between 2 and 4 days, along with an increase in blood HGF; and 2) appearance of BMDC in the tubules from 6 days postischemia. When anti-HGF IgG was injected in the earlier stage, tubular cell proliferation was inhibited, leading to an increase in BMDC in renal tubules. Under the HGF-neutralized state, stromal cell-derived factor-1 (SDF1) levels increased in renal tubules, associated with the enhanced hypoxia. Administrations of anti-SDF1 receptor IgG into ARF mice reduced the number of BMDC in interstitium and tubules. Thus possible cascades include 1) inhibition of tubular cell proliferation by neutralizing HGF leads to renal hypoxia and SDF1 upregulation; and 2) BMDC are eventually engrafted in tubules through SDF1-mediated chemotaxis. Inversely, administration of recombinant HGF suppressed the renal hypoxia, SDF1 upregulation, and BMDC engraftment in ARF mice by enhancing resident tubular cell proliferation. Thus we conclude that HGF is a positive regulator for eliciting resident tubular cell proliferation, and SDF1 for BMDC engraftment during the repair process of ARF.


1994 ◽  
Vol 36 (4) ◽  
pp. 392-395 ◽  
Author(s):  
TAKATSUGU KOJIMA ◽  
MISA SASAI-TAKEDATSU ◽  
YUKIO HIRATA ◽  
YOHNOSUKE KOBAYASHI

2018 ◽  
Vol 58 (2) ◽  
pp. 84-9
Author(s):  
Partini Pudjiastuti Trihono ◽  
Deasy Grafianti ◽  
Irawan Mangunatmadja ◽  
Mulya Rahma Karyanti

Background Long-term treatment with antiepileptic drugs such as valproic acid (VPA) and carbamazepine (CBZ) may disrupt renal tubular function. Urinary N-acetyl-beta-D-glucosaminidase (NAG) may reflect tubular function and may be useful in detecting early-stage tubular injury. To date, no study has investigated the toxic effect of VPA and CBZ on renal tubules using urinary NAG in Indonesian children. Objectives To determine the toxicity of long-term VPA and/or CBZ treatment on renal tubules in children with epilepsy by measuring urinary NAG index (iNAG). Methods This cross-sectional study was conducted from January to March 2015 at Cipto Mangunkusumo Hospital and Anakku Clinic Pondok Pinang, Jakarta. We included children aged 3 to 16 years with epilepsy on VPA (n=36), CBZ (n=14), or VPA-CBZ combination (n=14) therapy. We measured urinary levels of creatinine and NAG. The urinary NAG reference value was obtained from age-matched healthy controls (n=30). To eliminate diurnal variations in NAG, iNAG was calculated by dividing urinary NAG by urinary creatinine. A urinary iNAG of more than two standard deviations above the mean for healthy children was considered elevated. Results Mean urinary iNAG values for the control, VPA, CBZ, and combination groups were 3.01, 5.9, 4.07, and 6.9 U/g, respectively. All treated groups had higher mean urinary iNAG values compared to the control group. Urinary iNAG was increased in 11/36 children on VPA, 2/14 children on CBZ, and 9/14 children on combination therapy. Conclusion Long-term VPA use may impair renal tubular function, as shown by the increased urinary iNAG. Combination therapy increases damage in the renal tubules.


Peptides ◽  
1988 ◽  
Vol 9 (3) ◽  
pp. 595-600 ◽  
Author(s):  
S.C. Mah ◽  
S.E. Whitebread ◽  
M. De Gasparo ◽  
K.G. Hofbauer

2019 ◽  
Vol 16 (4) ◽  
pp. 0816
Author(s):  
Luma Qasim Ali

The present study aims to investigate the long-term histopathological, and physiological effects of different concentrations of a commercially available energy drink (Tiger) on liver and kidney of young mice. Sixteen Balb/c male mice,6 -week old, were divided into 4 groups (n=4). Two groups consumed the energy drink at a concentration of 28µl energy drink/ml water. One group were killed after 10 days (T1), another group were killed after 20 days (T2). Other group of mice consumed the energy drink at a final concentration of 14µl/ml for 20 days (T3). The last group was provided only with water and served as control. Mice of all groups drank around 3 ml per day. The histopathological study on liver of treated groups showed many changes such as inflammatory cells infiltration and aggregation with hepatocyts necrosis, some of these necrosis replaced by RBCs and inflammatory cells, while the pathohistological changes in kidney of treated groups limited to aggregation of RBCs and inflammatory cells between renal tubules which expressed vacuolar degeneration. These changes based on elevated liver function enzymes (Glutamic Oxaloacetic Transaminase (GOT), Glutamic Pyruvic Transaminase (GPT) and Alkaline phosphatase (ALP)) and blood urea and creatinine. These changes were more in the T2 groups, so it could be concluded that long term of energy drink consuming effect histopathologically and physiologically on kidney and liver of young mice depending on its concentration and period of consuming.


2017 ◽  
Vol 2017 ◽  
pp. 1-5 ◽  
Author(s):  
Renato Pascale ◽  
Viola Guardigni ◽  
Lorenzo Badia ◽  
Francesca Volpato ◽  
Pierluigi Viale ◽  
...  

Tenofovir disoproxil fumarate- (TDF-) related nephropathy is known to be a long-term complication of this drug, more commonly observed in HIV-infected patients, but occurring also in hepatitis B. Cases of Fanconi Syndrome associated with TDF have been reported in adult patients, usually as a long-term complication of chronic hepatitis B treatment. We present here a case of a 12-year-old male developing a severe acute HBV hepatitis treated with TDF. The patient achieved an early virological and biochemical response, but with a subsequent onset of proximal renal tubular damage, consistent with Fanconi Syndrome. After withdrawing this drug and switching to Entecavir, a complete resolution of tubulopathy and, after 6 months, a complete HBsAg seroconversion occurred. To our knowledge, this is the first report of an early renal injury due to TDF-therapy in a pediatric patient treated for acute hepatitis B.


2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e22013-e22013
Author(s):  
Elizabeth Fox ◽  
Christine Busch ◽  
Alexander DeBernardo ◽  
Kristin Levin ◽  
Yan Zhu ◽  
...  

e22013 Background: HDMTX AKI delays MTX excretion and increases the risk for severe systemic toxicity. MTX is thought to crystalize in renal tubules at urine [MTX] above the solubility limit, leading to AKI. Methods: Pharmacokinetic simulations of plasma and urine [MTX] at varying infusion durations (IDs) for 12 g/m2 MTX dose identified 12 h as the shortest duration with urine [MTX] below the solubility limit at pH 7.5. Using a randomized crossover design, we compared 4h and 12h IDs in patients with osteosarcoma treated with 12 g/m2 MTX. Urine AKI biomarkers (NAG, NGAL, KIM-1), urinalysis, and estimated glomerular filtration rate (GFR) were endpoints. [MTX] was measured in plasma using a commercial fluorescence polarization assay and in urine by HPLC. Results: Twelve patients, age 12.8 (5.6-19) y, received 12 g/m2 HDMTX over 4 h (40 infusions) and 12 h (35 infusions). At baseline (BL), GFR was 120 (100-175) mL/min/1.73m2; Median (range) NAG [21(5-64) U/gCr] and NGAL [11(0.7-325) µg/gCr] were normal and KIM-1 [0.9(0.4-6.3) µg/gCr] was elevated. Urine pH was maintained > 7 for all infusions. Proteinuria occurred during 93% of infusions. Table 1 compares 4h and 12h IDs. One patient had HDMTX AKI during a 12 h ID (data excluded from Table); end of infusion (EOI) [MTX] was 930 µM in plasma and 38 mM in urine. By 24h after the start of the HDMTX infusion, serum creatinine (sCr) was 1.4 mg/dL (3.5x BL), cystatin C was 1.0 (1.4x BL); NAG, NGAL and Kim-1 increased by > 350%. At 40h, plasma [MTX] was 40 µM; glucarpidase was administered. Plasma [MTX] < 0.1 µM was achieved at 310 h. Recovery to BL occurred at 20 d for sCr and 40 d for cystatin C. Conclusions: Transient proteinuria, increase in KIM-1 and NAG indicate acute proximal renal tubular damage in all HDMTX infusions regardless of ID. EOI urine [MTX] after 4 h or 12 h IDs did not exceed the solubility limit, including the patient with clinical HDMTX AKI. These results suggest that MTX crystallization in urine may not be the primary mechanism of HDMTX AKI. Clinical trial information: NCT01848457. [Table: see text]


2017 ◽  
Vol 312 (3) ◽  
pp. F502-F515 ◽  
Author(s):  
Yingfeng Shi ◽  
Liuqing Xu ◽  
Jinhua Tang ◽  
Lu Fang ◽  
Shuchen Ma ◽  
...  

Histone deacetylase 6 (HDAC6) inhibition has been reported to protect against ischemic stroke and prolong survival after sepsis in animal models. However, it remains unknown whether HDAC6 inhibition offers a renoprotective effect after acute kidney injury (AKI). In this study, we examined the effect of tubastatin A (TA), a highly selective inhibitor of HDAC6, on AKI in a murine model of glycerol (GL) injection-induced rhabdomyolysis. Following GL injection, the mice developed severe acute tubular injury as indicated by renal dysfunction; expression of neutrophil gelatinase-associated lipocalin (NGAL), an injury marker of renal tubules; and an increase of TdT-mediated dUTP nick-end labeling (TUNEL)-positive tubular cells. These changes were companied by increased HDAC6 expression in the cytoplasm of renal tubular cells. Administration of TA significantly reduced serum creatinine and blood urea nitrogen levels as well as attenuated renal tubular damage in injured kidneys. HDAC6 inhibition also resulted in decreased expression of NGAL, reduced apoptotic cell, and inactivated caspase-3 in the kidney after acute injury. Moreover, injury to the kidney increased phosphorylation of nuclear factor (NF)-κB and expression of multiple cytokines/chemokines including tumor necrotic factor-α and interleukin-6 and monocyte chemoattractant protein-1, as well as macrophage infiltration. Treatment with TA attenuated all those responses. Finally, HDAC6 inhibition reduced the level of oxidative stress by suppressing malondialdehyde (MDA) and preserving expression of superoxide dismutase (SOD) in the injured kidney. Collectively, these data indicate that HDAC6 contributes to the pathogenesis of rhabdomyolysis-induced AKI and suggest that HDAC6 inhibitors have therapeutic potential for AKI treatment.


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