Inhibition of tubular cell proliferation by neutralizing endogenous HGF leads to renal hypoxia and bone marrow-derived cell engraftment in acute renal failure

2008 ◽  
Vol 294 (2) ◽  
pp. F326-F335 ◽  
Author(s):  
Hiroyuki Ohnishi ◽  
Shinya Mizuno ◽  
Toshikazu Nakamura
Keyword(s):  
Bone Marrow ◽  
Cell Proliferation ◽  
Renal Failure ◽  
Acute Renal Failure ◽  
Repair Process ◽  
Tubular Cell ◽  
Tubular Damage ◽  
Renal Tubules ◽  
Stromal Cell Derived Factor ◽  
Renal Tubular

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.

scholarly journals The beneficial effects of thyroxine on nephrotoxic acute renal failure in the rat.

1991 ◽  
Vol 1 (11) ◽  
pp. 1236-1240
Author(s):  
U F Michael ◽  
J L Logan ◽  
L A Meeks
Keyword(s):  
Renal Failure ◽  
Acute Renal Failure ◽  
Potassium Dichromate ◽  
Fractional Excretion ◽  
Repair Process ◽  
Acid Extraction ◽  
Sprague Dawley ◽  
Beneficial Effects ◽  
Fractional Excretion Of Sodium ◽  
Renal Tubular

We were able to confirm previous studies demonstrating that administration of thyroxine is capable of ameliorating the severity of acute nephrotoxic renal failure in the rat. Nephrotoxic acute renal failure was induced by the subcutaneous injection of potassium dichromate (6.25 mg/kg) into Sprague-Dawley rats. Twenty-four hours after this injection, rats received an intraperitoneal injection of either thyroxine (80 micrograms/kg body wt) or normal saline. Forty-eight hours after the potassium dichromate injection, renal clearance studies were performed. Inulin clearance was significantly higher in the thyroxine-treated than in the saline-treated acute renal failure rats: 1.12 +/- 0.13 (SEM) mL/g versus 0.75 +/- 0.07 mL/min/g kidney wt (P = 0.025). Thyroxine treatment also effected an increase of p-aminohippuric acid extraction from 0.23 +/- 0.03 to 0.33 +/- 0.02 (P = 0.011) and a decrease in the fractional excretion of sodium from 0.38 +/- 0.21 to 0.11 +/- 0.03% (P = 0.037 by Mann-Whitney U test). In order to investigate one potential mechanism of the beneficial effect of thyroxine we studied renal tubular regeneration in this model of acute renal failure. Renal cortical uptake of labeled thymidine into DNA was significantly increased 48 h after the injection of potassium dichromate, and thyroxine administration further enhanced this repair process: 53.9 +/- 3.6 versus 81.4 +/- 5.3 dpm/200 pg of DNA (P = 0.0033).

scholarly journals Protease-Activated Receptor 1 Contributes to Microcirculation Failure and Tubular Damage in Renal Ischemia-Reperfusion Injury in Mice

2021 ◽  
Vol 2021 ◽  
pp. 1-8
Author(s):  
Yu Guan ◽  
Daisuke Nakano ◽  
Lei Li ◽  
Haofeng Zheng ◽  
Akira Nishiyama ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Cell Injury ◽  
Ischemia Reperfusion Injury ◽  
Cell Damage ◽  
Ischemia Reperfusion ◽  
Specific Treatment ◽  
Tubular Cell ◽  
Tubular Damage ◽  
Renal Tubules ◽  
Protease Activated Receptor 1

Ischemia-reperfusion- (IR-) induced kidney injury is difficult to avoid during renal transplantation and robot-assisted partial nephrectomy. Renal IR injury is characterized by tubular damage, microcirculation failure, and inflammation, which coordinately augment renal injury; however, no specific treatment is available for these conditions. Protease-activated receptor-1 (PAR-1) and its ligand, thrombin, are involved in coagulation and were shown to be associated with epithelial cell injury. Here, we hypothesized that PAR-1 exaggerated renal IR-induced tubular cell damage and microcirculation failure and that pharmacological inhibition of PAR-1 by Q94 could prevent these injuries. Renal warm IR increased the expression of PAR-1 in the renal tubules. Q94 attenuated renal IR-induced changes and histopathological damage. Microcirculation failure analyzed by congestion in the histopathology and blood cell flow examined by intravital multiphoton microscopy were suppressed by Q94 treatment. Q94 also dramatically increased tubular cell proliferation despite the lower renal damage. Thrombin suppressed cell proliferation and induced apoptosis in the tubules; these effects were prevented by Q94 treatment. Taken together, PAR-1 was associated with renal IR injury. Inhibition of PAR-1 ameliorated injury possibly by improving renal microcirculation and tubular cell survival/proliferation.

Promotion of cell proliferation by clusterin in the renal tissue repair phase after ischemia-reperfusion injury

2014 ◽  
Vol 306 (7) ◽  
pp. F724-F733 ◽  
Author(s):  
Christopher Y. C. Nguan ◽  
Qiunong Guan ◽  
Martin E. Gleave ◽  
Caigan Du
Keyword(s):  
Cell Proliferation ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Renal Tissue ◽  
Tubular Cell ◽  
Tubular Damage ◽  
Renal Repair ◽  
Renal Tubular ◽  
Repair Phase

Renal repair begins soon after the kidney suffers ischemia-reperfusion injury (IRI); however, its molecular pathways are not fully understood. Clusterin (Clu) is a chaperone protein with cytoprotective functions in renal IRI. The aim of this study was to investigate the role of Clu in renal repair after IRI. IRI was induced in the left kidneys of wild-type (WT) C57BL/6J (B6) vs. Clu knockout (KO) B6 mice by clamping the renal pedicles for 28–45 min at the body temperature of 32°C. The renal repair was assessed by histology and confirmed by renal function. Gene expression was examined using PCR array. Here, we show that following IRI, renal tubular damage and Clu expression in WT kidneys were induced at day 1, reached the maximum at day 3, and significantly diminished at day 7 along with normal function, whereas the tubular damage in Clu KO kidneys steadily increased from initiation of insult to the end of the experiment, when renal failure occurred. Renal repair in WT kidneys was positively correlated with an increase in Ki67+ proliferative tubular cells and survival from IRI. The functions of Clu in renal repair and renal tubular cell proliferation in cultures were associated with upregulation of a panel of genes that could positively regulate cell cycle progression and DNA damage repair, which might promote cell proliferation but not involve cell migration. In conclusion, these data suggest that Clu is required for renal tissue regeneration in the kidney repair phase after IRI, which is associated with promotion of tubular cell proliferation.

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 ◽  
...  
Keyword(s):  
Renal Failure ◽  
Arginine Vasopressin ◽  
Premature Death ◽  
Inflammatory Cells ◽  
Tubular Damage ◽  
Renal Tubules ◽  
Water Restriction ◽  
Primary Polydipsia ◽  
Renal Tubular

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.

scholarly journals AT1 and AT2 receptors modulate renal tubular cell necroptosis in angiotensin II-infused renal injury mice

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Yongjun Zhu ◽  
Hongwang Cui ◽  
Jie Lv ◽  
Haiqin Liang ◽  
Yanping Zheng ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Renal Injury ◽  
Critical Role ◽  
Kidney Injury ◽  
Renin Angiotensin System ◽  
Tubular Cell ◽  
Tubular Damage ◽  
Renal Tubular Cell ◽  
Ang Ii ◽  
Renal Tubular

AbstractAbnormal renin-angiotensin system (RAS) activation plays a critical role in the initiation and progression of chronic kidney disease (CKD) by directly mediating renal tubular cell apoptosis. Our previous study showed that necroptosis may play a more important role than apoptosis in mediating renal tubular cell loss in chronic renal injury rats, but the mechanism involved remains unknown. Here, we investigate whether blocking the angiotensin II type 1 receptor (AT1R) and/or angiotensin II type 2 receptor (AT2R) beneficially alleviates renal tubular cell necroptosis and chronic kidney injury. In an angiotensin II (Ang II)-induced renal injury mouse model, we found that blocking AT1R and AT2R effectively mitigates Ang II-induced increases in necroptotic tubular epithelial cell percentages, necroptosis-related RIP3 and MLKL protein expression, serum creatinine and blood urea nitrogen levels, and tubular damage scores. Furthermore, inhibition of AT1R and AT2R diminishes Ang II-induced necroptosis in HK-2 cells and the AT2 agonist CGP42112A increases the percentage of necroptotic HK-2 cells. In addition, the current study also demonstrates that Losartan and PD123319 effectively mitigated the Ang II-induced increases in Fas and FasL signaling molecule expression. Importantly, disruption of FasL significantly suppressed Ang II-induced increases in necroptotic HK-2 cell percentages, and necroptosis-related proteins. These results suggest that Fas and FasL, as subsequent signaling molecules of AT1R and AT2R, might involve in Ang II-induced necroptosis. Taken together, our results suggest that Ang II-induced necroptosis of renal tubular cell might be involved both AT1R and AT2R and the subsequent expression of Fas, FasL signaling. Thus, AT1R and AT2R might function as critical mediators.

Expression of SSAT, a novel biomarker of tubular cell damage, increases in kidney ischemia-reperfusion injury

2003 ◽  
Vol 284 (5) ◽  
pp. F1046-F1055 ◽  
Author(s):  
Kamyar Zahedi ◽  
Zhaohui Wang ◽  
Sharon Barone ◽  
Anne E. Prada ◽  
Caitlin N. Kelly ◽  
...  
Keyword(s):  
Renal Failure ◽  
Acute Renal Failure ◽  
Reperfusion Injury ◽  
Cell Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Atp Depletion ◽  
Tubular Cell ◽  
Mrna Levels ◽  
Tubular Injury

Ischemia-reperfusion injury (IRI) is the major cause of acute renal failure in native and allograft kidneys. Identifying the molecules and pathways involved in the pathophysiology of renal IRI will yield valuable new diagnostic and therapeutic information. To identify differentially regulated genes in renal IRI, RNA from rat kidneys subjected to an established renal IRI protocol (bilateral occlusion of renal pedicles for 30 min followed by reperfusion) and time-matched kidneys from sham-operated animals was subjected to suppression subtractive hybridization. The level of spermidine/spermine N 1-acetyltransferase (SSAT) mRNA, an essential enzyme for the catabolism of polyamines, increased in renal IRI. SSAT expression was found throughout normal kidney tubules, as detected by nephron segment RT-PCR. Northern blots demonstrated that the mRNA levels of SSAT are increased by greater than threefold in the renal cortex and by fivefold in the renal medulla at 12 h and returned to baseline at 48 h after ischemia. The increase in SSAT mRNA was paralleled by an increase in SSAT protein levels as determined by Western blot analysis. The concentration of putrescine in the kidney increased by ∼4- and ∼7.5-fold at 12 and 24 h of reperfusion, respectively, consistent with increased functional activity of SSAT. To assess the specificity of SSAT for tubular injury, a model of acute renal failure from Na+depletion (without tubular injury) was studied; SSAT mRNA levels remained unchanged in rats subjected to Na+ depletion. To distinguish SSAT increases from the effects of tubular injury vs. uremic toxins, SSAT was increased in cis-platinum-treated animals before the onset of renal failure. The expression of SSAT mRNA and protein increased by ∼3.5- and >10-fold, respectively, in renal tubule epithelial cells subjected to ATP depletion and metabolic poisoning (an in vitro model of kidney IRI). Our results suggest that SSAT is likely a new marker of tubular cell injury that distinguishes acute prerenal from intrarenal failure.

Recovery from Acute Ischaemic Renal Failure is Accelerated by Des-(1–3)-Insulin-Like Growth Factor-1

1994 ◽  
Vol 86 (6) ◽  
pp. 709-714 ◽  
Author(s):  
Ross Clark ◽  
Deborah Mortensen ◽  
Ralph Rabkin
Keyword(s):  
Renal Failure ◽  
Acute Renal Failure ◽  
Growth Factor ◽  
Fractional Excretion ◽  
Insulin Like Growth Factor ◽  
Ischaemic Injury ◽  
Beneficial Effects ◽  
Nitrogen Levels ◽  
Renal Tubular Cells ◽  
Renal Tubular

1. Acute renal failure carries a high risk of morbidity and mortality, so there is a need for agents that minimize renal injury after an insult and that hasten repair. Insulin-like growth factor-1 is mitogenic for renal tubular cells; in normal kidneys it has haemodynamic effects and it is potently anabolic. We tested the theory that insulin-like growth factor-1 may be of use in the treatment of acute renal failure by administering recombinant des-(1–3)-insulin-like growth factor-1, a truncated form of insulin-like growth factor-1, which occurs naturally. Ischaemic renal failure was induced in normal rats by occluding both renal pedicles for 60 min. Then des-(1–3)-insulin-like growth factor-1 (0.8 mg day−1 kg−1) or vehicle was given by subcutaneous minipump for 7 days. The rats were weighed and bled daily and in one experiment were housed in metabolic cages and urine was collected. 2. Des-(1–3)-insulin-like growth factor-1 caused a lower and earlier peak in both serum creatinine and blood urea-nitrogen levels, and a more rapid and complete return toward basal values than in untreated animals. Also des-(1–3)-insulin-like growth factor-1 significantly increased creatinine clearance and reduced fractional excretion of filtered sodium. Besides these beneficial effects on kidney function, des-(1–3)-insulin-like growth factor-1 was anabolic as treated rats gained weight while control rats lost weight. The mortality in control rats was 28% compared with 6% in treated rats. 3. Thus des-(1–3)-insulin-like growth factor-1 accelerated recovery from acute ischaemic injury and may be useful for the treatment of acute renal failure.

Sign in / Sign up

Export Citation Format

Share Document