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Proteinuria impairs podocyte regeneration by sequestering retinoic acid
Anna Peired1, Maria Lucia Angelotti, Elisa Ronconi
1Excellence Centre for Research, Transfer and High Education for the Development of DE NOVO Therapies (DENOTHE) and.
Journal of the American Society of Nephrology : JASN
|August 17, 2013
Summary
Proteinuria, particularly albumin, impairs kidney podocyte regeneration by sequestering retinoic acid, worsening glomerulosclerosis in chronic kidney disease (CKD). Retinoic acid treatment improved podocyte number and reduced proteinuria in models.
Area of Science:
- Nephrology
- Cell Biology
- Molecular Medicine
Background:
- Chronic kidney disease (CKD) progression is linked to proteinuria and podocyte loss.
- Understanding the direct role of proteinuria in glomerulosclerosis is crucial for developing targeted therapies.
Purpose of the Study:
- To investigate if proteinuria directly promotes glomerulosclerosis by inhibiting podocyte regeneration.
- To elucidate the specific mechanisms by which albuminuria affects renal progenitor cells.
Main Methods:
- In vitro studies using human renal progenitors and retinoic acid response element (RARE) reporter assays.
- In vivo studies using mouse models of Adriamycin nephropathy and genetic podocyte labeling (NPHS2.Cre;mT/mG, RARE-lacZ).
- Analysis of serial biopsy specimens following retinoic acid treatment.
Main Results:
- Albumin in proteinuria sequestered retinoic acid, preventing differentiation of renal progenitors into podocytes by inhibiting RARE-mediated transcription.
- Blocking retinoic acid synthesis in mice exacerbated proteinuria and glomerulosclerosis, linked to reduced podocyte numbers.
- Retinoic acid treatment restored RARE activity, promoted podocyte differentiation, decreased proteinuria, and increased podocyte numbers in vivo.
Conclusions:
- Albuminuria impairs podocyte regeneration by depleting retinoic acid, contributing to focal segmental glomerulosclerosis (FSGS) development.
- These findings provide a biological basis for reducing proteinuria to slow CKD progression.
- Targeting retinoic acid signaling offers a potential therapeutic strategy for glomerular diseases.
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