Podocyte Repopulation Contributes to Regression of Glomerular Injury Induced by Ace Inhibition

Macconi, Daniela; Sangalli, Fabio; Bonomelli, Maria; Conti, Sara; Condorelli, Lucia; Gagliardini, Elena; Remuzzi, Giuseppe; Remuzzi, Andrea

doi:10.2353/ajpath.2009.080227

Cited by 93 publications

(90 citation statements)

References 42 publications

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“…As shown in Table 1, consistently with BASIC RESEARCH www.jasn.org previous data, 24 40-week-old MWF rats showed a significantly higher (P Ͻ 0.05) systolic BP than Wistar rats, heavy proteinuria (P Ͻ 0.05, MWF versus Wistar), and impaired renal function. Representative images at optical microscopy of histologic cortical renal lesions in these animals, with signs of glomerulosclerosis, are reported in Figure 5B.…”

Section: Renal Histology In Mwf Ratssupporting

confidence: 77%

Imaging of the Porous Ultrastructure of the Glomerular Epithelial Filtration Slit

Gagliardini

Conti

Benigni

et al. 2010

Journal of the American Society of Nephrology

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The ultrastructure of the glomerular filtration slit is still controversial. In the last 30 years, observations from transmission electron microscopy (TEM) and theoretical analysis of solute clearance produced conflicting results. Here, we used scanning EM with a high-sensitivity detector to image the deepest regions of the filtration slits and report a previously undescribed organization of the slits' ultrastructure. In contrast to previous TEM imaging, we observed circular and ellipsoidal pores in the podocyte junctions mainly located in the central region of the slit diaphragm. The normal mean pore radius estimated by digital morphometric analysis had a log-normal distribution, with an average value of 12.1 nm. In proteinuric pathologic conditions, the mean pore radius values were also log-normally distributed with the presence of some very large pores, exceeding the sizes observed in normal conditions. Our morphologic analysis suggests that the filtration slit is a heteroporous structure instead of the previously proposed zipper-like structure. Selective changes in the ultrastructural organization of the pores may be responsible for the increased filtration of plasma proteins in glomerular disease. The permeability properties of the glomerular capillary wall allow the filtration of high water flow and small solutes but efficient retention of plasma proteins the size of albumin or larger. 1 It has been indicated that most of the restriction of macromolecule ultrafiltration is caused by the epithelial filtration slits, because plasma proteins can cross endothelial cells and glomerular basement membrane (GBM) more easily. 2 Changes in glomerular permselective function resulting in increased glomerular filtration of plasma proteins and incomplete tubular reabsorption are responsible for loss of proteins in the urine. These events have been linked to the progression of renal diseases. 3 With the aim to characterize the mechanisms behind proteinuria, in the last 30 years, solute clearance techniques have been used to estimate the selective properties of the glomerular barrier in experimental models of nephropathy and in patients. In particular, glomerular size-selective function has been studied using renal clearance of neutral test macromolecules (i.e., neutral dextran and Ficoll) that are not secreted or reabsorbed at the tubular level. Theoretical models of glomerular size selectivity have been conventionally used to derive intrinsic membrane selective properties from fractional clearance of test macromolecules in terms of density and size of hypothetical pores perforating the glomerular capillary wall. 2,4,5 Thus, according to the two-pore

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Section: Renal Histology In Mwf Ratssupporting

confidence: 77%

Imaging of the Porous Ultrastructure of the Glomerular Epithelial Filtration Slit

Gagliardini

Conti

Benigni

et al. 2010

Journal of the American Society of Nephrology

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“…6,11,12,33 Notably, a previous study reported that mouse treatment with ACE inhibitors induced regression of FSGS lesions and increased expression of podocyte markers by RPCs and podocyte number, suggesting that remodeling of RPCs is a key feature of ACE inhibitor renoprotection. 34,35 Finally, our results also suggest that when both albuminuria and larger proteins, such as IgG and transferrin, are lost, a combined toxic effect not only blocks RPC differentiation into podocytes but also promotes their death. This potentially explains the observation that when nonselective proteinuria occurs, renal function declines faster.…”

Section: Discussionmentioning

confidence: 64%

Proteinuria Impairs Podocyte Regeneration by Sequestering Retinoic Acid

Peired¹,

Angelotti²,

Ronconi³

et al. 2013

Journal of the American Society of Nephrology

121

110

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In CKD, the risk of kidney failure and death depends on the severity of proteinuria, which correlates with the extent of podocyte loss and glomerular scarring. We investigated whether proteinuria contributes directly to progressive glomerulosclerosis through the suppression of podocyte regeneration and found that individual components of proteinuria exert distinct effects on renal progenitor survival and differentiation toward a podocyte lineage. In particular, albumin prevented podocyte differentiation from human renal progenitors in vitro by sequestering retinoic acid, thus impairing retinoic acid response element (RARE)-mediated transcription of podocyte-specific genes. In mice with Adriamycin nephropathy, a model of human FSGS, blocking endogenous retinoic acid synthesis increased proteinuria and exacerbated glomerulosclerosis. This effect was related to a reduction in podocyte number, as validated through genetic podocyte labeling in NPHS2.Cre;mT/mG transgenic mice. In RARE-lacZ transgenic mice, albuminuria reduced retinoic acid bioavailability and impaired RARE activation in renal progenitors, inhibiting their differentiation into podocytes. Treatment with retinoic acid restored RARE activity and induced the expression of podocyte markers in renal progenitors, decreasing proteinuria and increasing podocyte number, as demonstrated in serial biopsy specimens. These results suggest that albumin loss through the damaged filtration barrier impairs podocyte regeneration by sequestering retinoic acid and promotes the generation of FSGS lesions. Our findings may explain why reducing proteinuria delays CKD progression and provide a biologic rationale for the clinical use of pharmacologic modulators to induce regression of glomerular diseases.

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“…The replacement of lost podocytes by activated parietal epithelial cells is a compensatory mechanism that, if successful, is accompanied by remodeling the glomerular architecture (25). However, under certain conditions, this replacement mechanism cannot compensate fully, thereby leading to renal damage that is histologically characterized by FSGS.…”

Section: Discussionmentioning

confidence: 99%

Association of Preeclampsia with Podocyte Turnover

Penning¹,

Bloemenkamp

Zon³

et al. 2014

Clinical Journal of the American Society of Nephrology

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Background and objectives Preeclampsia is characterized by hypertension and proteinuria, and increased shedding of podocytes into the urine is a common finding. This finding raises the question of whether preeclamptic nephropathy involves podocyte damage. This study examined podocyte-related changes in a unique sample of renal tissues obtained from women who died of preeclampsia.Design, setting, participants, & measurements All patients with preeclampsia who died in The Netherlands since 1990 and had available autopsy tissue were identified using a nationwide database of the Dutch Pathology Registry (PALGA). This resulted in a cohort of 11 women who died from preeclampsia. Three control groups were also identified during the same time period, and consisted of normotensive women who died during pregnancy (n=25), and nonpregnant controls either with (n=14) or without (n=13) chronic hypertension. Glomerular lesions, including podocyte numbers, podocyte proliferation, and parietal cell activation, were measured.Results Patients with preeclampsia had prominent characteristic glomerular lesions. The results showed that the number of podocytes per glomerulus did not differ significantly between the patients with preeclampsia and the control groups. However, preeclampsia was associated with a significant increase in intraglomerular cell proliferation (7.3% [SD 9.4] Conclusions These findings suggest that the recently described mechanisms of podocyte replacement play a role in preeclampsia. These results provide key new insights into the pathogenesis of preeclamptic nephropathy, and they open new possibilities for developing therapeutic modalities.

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Podocyte Repopulation Contributes to Regression of Glomerular Injury Induced by Ace Inhibition

Cited by 93 publications

References 42 publications

Imaging of the Porous Ultrastructure of the Glomerular Epithelial Filtration Slit

Imaging of the Porous Ultrastructure of the Glomerular Epithelial Filtration Slit

Proteinuria Impairs Podocyte Regeneration by Sequestering Retinoic Acid

Association of Preeclampsia with Podocyte Turnover

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