Diminished Met Signaling in Podocytes Contributes to the Development of Podocytopenia in Transplant Glomerulopathy

Agustian, Putri A.; Schiffer, Mario; Gwinner, Wilfried; Schäfer, Irini; Theophile, Katharina; Modde, Friedrich; Bockmeyer, Clemens L.; Traeder, Jana; Lehmann, Ulrich; Groβhennig, Anika; Kreipe, Hans; Bröcker, Verena; Becker, Jan U.

doi:10.1016/j.ajpath.2011.01.042

Cited by 11 publications

(8 citation statements)

References 88 publications

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“…We would expect that this high level of podocyte detachment, if persistent, would be associated with progressive podocyte depletion and progression to ESRD over time, particularly because kidney allograft recipients have only one kidney and thus half the number of podocytes compared with the 2K state. In keeping with this expectation, biopsies from patients with late TG (average 10.6 years after grafting) showed a highly significant reduction in podocyte density caused by a 20 and podocyte injury/stress was previously reported in a rat model of kidney transplantation. 21 Similar reductions in podocyte density have also been reported for both diabetic glomerulosclerosis and IgA nephropathy.…”

Section: Discussionmentioning

confidence: 62%

The Two Kidney to One Kidney Transition and Transplant Glomerulopathy

Yang¹,

Hodgin²,

Afshinnia³

et al. 2015

Journal of the American Society of Nephrology

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The attrition rate of functioning allografts beyond the first year has not improved despite improved immunosuppression, suggesting that nonimmune mechanisms could be involved. Notably, glomerulopathies may account for about 40% of failed kidney allografts beyond the first year of engraftment, and glomerulosclerosis and progression to ESRD are caused by podocyte depletion. Model systems demonstrate that nephrectomy can precipitate hypertrophic podocyte stress that triggers progressive podocyte depletion leading to ESRD, and that this process is accompanied by accelerated podocyte detachment that can be measured in urine. Here, we show that kidney transplantation "reverse nephrectomy" is also associated with podocyte hypertrophy and increased podocyte detachment. Patients with stable normal allograft function and no proteinuria had levels of podocyte detachment similar to levels in two-kidney controls as measured by urine podocyte assay. By contrast, patients who developed transplant glomerulopathy had 10-to 20-fold increased levels of podocyte detachment. Morphometric studies showed that a subset of these patients developed reduced glomerular podocyte density within 2 years of transplantation due to reduced podocyte number per glomerulus. A second subset developed glomerulopathy by an average of 10 years after transplantation due to reduced glomerular podocyte number and glomerular tuft enlargement. Reduced podocyte density was associated with reduced eGFR, glomerulosclerosis, and proteinuria. These data are compatible with the hypothesis that podocyte depletion contributes to allograft failure and reduced allograft half-life. Mechanisms may include immune-driven processes affecting the podocyte or other cells and/or hypertrophy-induced podocyte stress causing accelerated podocyte detachment, which would be amenable to nonimmune therapeutic targeting. Podocytes are complex neuron-like postmitotic cells adherent to the underlying glomerular basement membrane via foot processes that must contiguously cover the filtration surface area to maintain the normal filtration barrier. Podocytes cannot divide in situ and have limited capacity for replacement. 1 This means that when podocytes are lost, or the glomerular surface area increases due to glomerular growth, the major adaptive response is by hypertrophy. At the same time, the podocyte's structural complexity means that its capacity to hypertrophy is limited. Inability to maintain contiguous coverage of the filtration surface by foot processes results in protein leak into the filtrate. If podocyte detachment exceeds hypertrophic capacity, other glomerular cells adapt by proliferating and laying down matrix resulting in glomerulosclerosis. [2][3][4][5][6]

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Section: Discussionmentioning

confidence: 62%

The Two Kidney to One Kidney Transition and Transplant Glomerulopathy

Yang¹,

Hodgin²,

Afshinnia³

et al. 2015

Journal of the American Society of Nephrology

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“…While the rapid activation of autophagy is thought to occur mainly via changes in kinase activity, the chronic administration of mTOR inhibitors can induce transcriptional changes of autophagy related genes ( 14 , 15 ). In order to investigate whether podocytic changes seen with TEM were paralleled by changes in gene expression we performed laser capture microdissection of glomeruli ( Figure 2A,B ), thereby enriching podocytic transcripts for expression analysis by quantitative RT-PCR ( 16 ). Expression levels of all tested genes ( Atg5 , Beclin1 and Gabarapl1 ) showed no discernible differences between the groups ( Figure 2C ) indicating that changes seen in TEM were not paralleled by increased transcription of autophagy pathway genes.…”

Section: Resultsmentioning

confidence: 99%

Autophagy in kidney transplants of sirolimus treated recipients

et al. 2016

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BackgroundMammalian target of rapamycin (mTOR) inhibitors are increasingly used as immunosuppressive agents in kidney transplantation. In the experimental setting it has been shown that mTOR inhibitors promote autophagy, but the concept that this might also occur in transplant patients has not been addressed.ObjectivesThis study was designed to investigate the association between mTOR inhibition and autophagy in renal transplants under routine clinical conditions.Materials and MethodsProtocol transplant biopsies of patients receiving sirolimus were compared to biopsies of patients treated without mTOR inhibitor. Electron microscopy was used for quantitative stereological analysis of autophagosomal volume fractions. Ultrastructural analysis was focused on podocytes to avoid cell type bias. Autophagy-related gene products were profiled by QPCR from laser assisted microdissected glomeruli and by immunohistochemistry for semiquantitative evaluation.ResultsBy electron microscopy, we observed a significant > 50% increase in podocytic autophagosomal volume fractions in patients treated with sirolimus. Evaluation of biopsy material from the same patients using transcriptional profiling of laser capture microdissected glomeruli revealed no differences in autophagy-related gene expressions. Immunohistochemical evaluation of autophagic degradation product p62 was also unaltered whereas a significant increase was observed in podocytic LC3 positivity in biopsies of sirolimus treated patients.ConclusionsThese results indicate an association of sirolimus treatment and autophagosome formation in transplant patients. However, they might reflect autophagosomal buildup rather than increased autophagic flux. Further research is needed to investigate the potential functional consequences in short- and long-term outcome of patients treated with mTOR inhibitors.

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“…Stimulation of podocytes with HGF in vitro resulted in antiapoptotic phosphorylation of AKT and extracellular signal-regulated kinase and induction of the X-linked inhibitor of apoptosis protein. In the same study, diminution of the HGF downstream signaling pathway in podocytes contributes to cell loss and FSGS in transplant glomerulopathy [ 42 ]. However, evidence from uPA and uPAR deficient animals has shown other molecules, such as vitronectin and high molecular weight kininogen, are alternate uPAR ligands, and receptors in addition to uPAR may also bind directly to uPA and activate cell signaling pathways [ 43 ].…”

Section: Discussionmentioning

confidence: 99%

Significance of the urokinase-type plasminogen activator and its receptor in the progression of focal segmental glomerulosclerosis in clinical and mouse models

Chen

Chang

et al. 2016

J Biomed Sci

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BackgroundsuPAR biomarker generally considered a pathogenic factor in FSGS. However, studies have been published that dispute this conclusion. The current study was designed to investigate the roles of uPA and suPAR in FSGS in clinical and mouse models.MethodsClinical subjects including those with biopsy-proven FSGS and MCD were enrolled. To verify the role of uPA in FSGS, Adriamycin was used to induce FSGS in uPA knockout (uPA−/−) and BALB/c (WT) mice. Proteinuria and suPAR, the cleaved/intact forms of the circulating suPAR, and possible proteases involving cleavage of the suPAR were also studied.ResultsFSGS clinical cases presented significantly higher serum levels of suPAR and Cr and lower serum levels of uPA. In the mice model, the uPA−/− group exhibited faster disease progression and worsening proteinuria than the WT group. In addition, the uPA−/− group had higher plasma suPAR levels, glomerular cell apoptosis, and dysregulation of the Th1/Th2 balance. In an analysis of suPAR variants in FSGS, both the intact and cleaved forms of the suPAR were higher in clinical subjects and the mouse model. However, the process of suPAR cleavage was not mediated by enzymatic activities of the uPA, elastase, or cathepsin G.ConclusionsA deficiency of uPA accelerated the progression of Adriamycin-induced mouse FSGS model. Decrease of serum uPA levels may be an indicator of the progression of FSGS in clinical subjects and animal models.

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Diminished Met Signaling in Podocytes Contributes to the Development of Podocytopenia in Transplant Glomerulopathy

Cited by 11 publications

References 88 publications

The Two Kidney to One Kidney Transition and Transplant Glomerulopathy

The Two Kidney to One Kidney Transition and Transplant Glomerulopathy

Autophagy in kidney transplants of sirolimus treated recipients

Significance of the urokinase-type plasminogen activator and its receptor in the progression of focal segmental glomerulosclerosis in clinical and mouse models

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