The Contribution of Podocytes to Chronic Allograft Nephropathy

Pippin, Jeffrey W.; Kumar, Vineeta; Stein, Alicia; Jablonski, Paula; Shankland, Stuart J.; Davis, Connie L.

doi:10.1159/000178762

Cited by 18 publications

(22 citation statements)

References 90 publications

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“…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. 22,23 Podocyte nuclear density was related to eGFR at the time of biopsy compatible with podocyte depletion causing progression to ESRD, as has been proven to occur in model systems.…”

Section: Discussionsupporting

confidence: 63%

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: Discussionsupporting

confidence: 63%

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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“…10 Podocyte damage leading via podocytopenia to FSGS is thought to play a pivotal role in the progression of glomerular diseases to FSGS. 2,11,12 This has been documented in human IgA glomerulonephritis, 13 hypertensive glomerulopathy, 14 diabetic nephropathy, 15,16 and animal models of transplant glomerulopathy, 17 and membranous 18 and immune complex glomerulonephritis. 19 Therefore, a considerable research effort has been undertaken recently to examine podocyte replacement by extrarenal and also intrarenal progenitors.…”

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confidence: 99%

Bone Marrow–Derived Progenitor Cells Do Not Contribute to Podocyte Turnover in the Puromycin Aminoglycoside and Renal Ablation Models in Rats

Meyer-Schwesinger

Lange

Bröcker

et al. 2011

The American Journal of Pathology

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A key event in the progression of glomerular disease is podocyte loss that leads to focal and segmental glomerulosclerosis (FSGS). Because adult podocytes are postmitotic cells, podocyte replacement by bone marrow-derived progenitors could prevent podocytopenia and FSGS. This study uses double immunofluorescence for Wilms' tumor-1 and enhanced green fluorescent protein (eGFP) to examine whether an eGFP-positive bone marrow transplant can replace podocytes under normal circumstances and in 3 different rat models of FSGS: puromycin aminoglycoside nephropathy, subtotal nephrectomy, and uninephrectomy. Bone marrow engraftment was successful, with more than 70% eGFPpositive cells and virtually normal histologic findings. No bone marrow transplant-derived podocytes were found in four control rats after transplantation, in nine rats at up to 10 weeks after puromycin aminoglycoside nephropathy induction, in three rats 23 days after subtotal nephrectomy, and in six rats up to 21 days after uninephrectomy. A total of 2200 glomeruli with 14,474 podocytes were evaluated in all groups. Thus, podocyte replacement by bone marrow-derived cells does not contribute to podocyte turnover in rats, even in models of podocyte damage. This is in contrast to previous studies in mice, in which bone marrow-derived podocytes were found. Further studies will address this discrepancy, which could be explained by species differences or by predominant podocyte regeneration from a parietal epithelial cell niche.

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“…In rats, mild renal I/R has been reported to cause a decrease in glomerular filtration barrier (GFB) charge and size selectivity, proteinuria and podocyte effacement (Rippe et al, 2006;Andersson et al, 2007;Wagner et al, 2008). More prolonged insults, typically associated with organ preservation before transplantation, can cause severe glomerular lesions including podocyte loss and glomerulosclerosis (Lambert et al, 1986;Pippin et al, 2009). In patients, marked proteinuria has been reported during the initial hours after renal transplantation (Stefanidis et al, 1996).…”

Section: Introductionmentioning

confidence: 99%

The subtypes of peroxisome proliferator‐activated receptors expressed by human podocytes and their role in decreasing podocyte injury

Miglio

Rosa

Rattazzi

et al. 2010

British J Pharmacology

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BACKGROUND AND PURPOSEPeroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors, and three subtypes (a, b and g) have been identified. PPAR activation has been reported to decrease renal injury and markers of glomerular dysfunction in models of renal ischemia/reperfusion (I/R). However, both the I/R effects and the effects of PPAR agonists on podocytes, an integral cellular part of the glomerular filtration barrier, remain to be established. EXPERIMENTAL APPROACHBy using oxygen/glucose deprivation-reoxygenation as an in vitro model that mimics in vivo I/R, the effects of PPAR agonists on podocyte death were compared. Human immortalized podocytes were treated with gemfibrozil, GW0742, pioglitazone or rosiglitazone, as a single or repeated challenge. Cell loss, necrotic and apoptotic cell death were measured. KEY RESULTSOnly the repeated treatment with each PPAR agonist significantly prevented cell death, mainly by decreasing apoptosis. In comparison, in a model of serum deprivation-induced apoptosis, both treatments were effective, although the repeated treatment achieved the more pronounced effect. Finally, our results showed that preservation of Bcl-2, Bax and nephrin expression accompanied the anti-apoptotic effects exerted by PPAR agonists in human podocytes. CONCLUSION AND IMPLICATIONSThese findings contribute to clarification of the pathophysiological role of renal PPARs and suggest that selective PPARa, PPARb or PPARg agonists may exert similar protective effects on podocytes by decreasing apoptotic cell death. Abbreviations

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The Contribution of Podocytes to Chronic Allograft Nephropathy

Cited by 18 publications

References 90 publications

The Two Kidney to One Kidney Transition and Transplant Glomerulopathy

The Two Kidney to One Kidney Transition and Transplant Glomerulopathy

Bone Marrow–Derived Progenitor Cells Do Not Contribute to Podocyte Turnover in the Puromycin Aminoglycoside and Renal Ablation Models in Rats

The subtypes of peroxisome proliferator‐activated receptors expressed by human podocytes and their role in decreasing podocyte injury

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