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Proteinuria impairs podocyte regeneration by sequestering retinoic acid

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Proteinuria impairs podocyte regeneration by sequestering retinoic acid. / Peired, Anna; Angelotti, Maria Lucia; Ronconi, Elisa; la Marca, Giancarlo; Mazzinghi, Benedetta; Sisti, Alessandro; Lombardi, Duccio; Giocaliere, Elisa; Della Bona, Marialuisa; Villanelli, Fabio; Parente, Eliana; Ballerini, Lara; Sagrinati, Costanza; Wanner, Nicola; Huber, Tobias B; Liapis, Helen; Lazzeri, Elena; Lasagni, Laura; Romagnani, Paola.

In: J AM SOC NEPHROL, Vol. 24, No. 11, 11.2013, p. 1756-68.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Peired, A, Angelotti, ML, Ronconi, E, la Marca, G, Mazzinghi, B, Sisti, A, Lombardi, D, Giocaliere, E, Della Bona, M, Villanelli, F, Parente, E, Ballerini, L, Sagrinati, C, Wanner, N, Huber, TB, Liapis, H, Lazzeri, E, Lasagni, L & Romagnani, P 2013, 'Proteinuria impairs podocyte regeneration by sequestering retinoic acid', J AM SOC NEPHROL, vol. 24, no. 11, pp. 1756-68. https://doi.org/10.1681/ASN.2012090950

APA

Peired, A., Angelotti, M. L., Ronconi, E., la Marca, G., Mazzinghi, B., Sisti, A., Lombardi, D., Giocaliere, E., Della Bona, M., Villanelli, F., Parente, E., Ballerini, L., Sagrinati, C., Wanner, N., Huber, T. B., Liapis, H., Lazzeri, E., Lasagni, L., & Romagnani, P. (2013). Proteinuria impairs podocyte regeneration by sequestering retinoic acid. J AM SOC NEPHROL, 24(11), 1756-68. https://doi.org/10.1681/ASN.2012090950

Vancouver

Peired A, Angelotti ML, Ronconi E, la Marca G, Mazzinghi B, Sisti A et al. Proteinuria impairs podocyte regeneration by sequestering retinoic acid. J AM SOC NEPHROL. 2013 Nov;24(11):1756-68. https://doi.org/10.1681/ASN.2012090950

Bibtex

@article{fa8b50f4ca844a7f87a51a848fd96ef3,
title = "Proteinuria impairs podocyte regeneration by sequestering retinoic acid",
abstract = "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.",
keywords = "Albuminuria, Animals, Cells, Cultured, Female, Glomerulosclerosis, Focal Segmental, Humans, Mice, Mice, SCID, Podocytes, Regeneration, Response Elements, Tretinoin, Journal Article, Research Support, Non-U.S. Gov't",
author = "Anna Peired and Angelotti, {Maria Lucia} and Elisa Ronconi and {la Marca}, Giancarlo and Benedetta Mazzinghi and Alessandro Sisti and Duccio Lombardi and Elisa Giocaliere and {Della Bona}, Marialuisa and Fabio Villanelli and Eliana Parente and Lara Ballerini and Costanza Sagrinati and Nicola Wanner and Huber, {Tobias B} and Helen Liapis and Elena Lazzeri and Laura Lasagni and Paola Romagnani",
year = "2013",
month = nov,
doi = "10.1681/ASN.2012090950",
language = "English",
volume = "24",
pages = "1756--68",
journal = "J AM SOC NEPHROL",
issn = "1046-6673",
publisher = "American Society of Nephrology",
number = "11",

}

RIS

TY - JOUR

T1 - Proteinuria impairs podocyte regeneration by sequestering retinoic acid

AU - Peired, Anna

AU - Angelotti, Maria Lucia

AU - Ronconi, Elisa

AU - la Marca, Giancarlo

AU - Mazzinghi, Benedetta

AU - Sisti, Alessandro

AU - Lombardi, Duccio

AU - Giocaliere, Elisa

AU - Della Bona, Marialuisa

AU - Villanelli, Fabio

AU - Parente, Eliana

AU - Ballerini, Lara

AU - Sagrinati, Costanza

AU - Wanner, Nicola

AU - Huber, Tobias B

AU - Liapis, Helen

AU - Lazzeri, Elena

AU - Lasagni, Laura

AU - Romagnani, Paola

PY - 2013/11

Y1 - 2013/11

N2 - 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.

AB - 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.

KW - Albuminuria

KW - Animals

KW - Cells, Cultured

KW - Female

KW - Glomerulosclerosis, Focal Segmental

KW - Humans

KW - Mice

KW - Mice, SCID

KW - Podocytes

KW - Regeneration

KW - Response Elements

KW - Tretinoin

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

U2 - 10.1681/ASN.2012090950

DO - 10.1681/ASN.2012090950

M3 - SCORING: Journal article

C2 - 23949798

VL - 24

SP - 1756

EP - 1768

JO - J AM SOC NEPHROL

JF - J AM SOC NEPHROL

SN - 1046-6673

IS - 11

ER -