Retinoic acid receptor β deletion in podocytes causes kidney and liver dysfunction, modeling nephrotic syndrome
Yuling Chi1, Krysta M DiKun1, Xiao-Han Tang1
1Pharmacology Department, Weill Cornell Medicine of Cornell University, New York, New York, USA.
Abstract:
Differentially altered expression of transcripts of retinoic acid receptors α, β, γ (Rarα, β, γ), which mediate the actions of all-trans retinoic acid (RA), is observed in glomeruli of nephrotic syndrome (NS) patients vs normal individuals, with Rarβ reduced and both RARα and RARγ increased. Thus, we generated a mouse model (PCRB) with Rarβ specifically deleted in podocytes to define the glomerular actions of Rarβ. Rarβ deletion in PCRB mice results in podocyte loss, podocyte foot process effacement, glomerular basement membrane (GBM) thickening, reduced podocyte adhesion to the GBM, lipid accumulation in glomeruli, and hyperfiltration leading to albuminuria. Genome-wide transcriptomics and proteomics studies of glomeruli revealed that Rarβ deletion increased Mogat, Dgat, and Hmgcs mRNAs, which catalyze triglyceride and cholesterol synthesis, and Slc27a2 and Cd36, which mediate fatty acid uptake, recapitulating NS symptoms. Surprisingly, podocyte-specific Rarβ deletion also increased key mRNAs and proteins involved in fatty acid uptake and lipid biosynthesis in the liver, promoting steatohepatitis and systemic hyperlipidemia. These data indicate that Rarβ signaling in the kidney has a profound impact on both kidney and liver functions and suggest that Rarβ plays an important role in regulating kidney-liver crosstalk. PCRB mice may be a useful model of NS.
Insights
Podocyte-specific deletion of retinoic acid receptor beta (Rarβ) in mice causes nephrotic syndrome and liver disease. This highlights Rarβ
Area of Science:
- Nephrology
- Endocrinology
- Molecular Biology
Background:
- Retinoic acid receptors (RARs) α, β, and γ (Rarα, β, γ) mediate all-trans retinoic acid (RA) actions.
- Altered RAR expression is observed in nephrotic syndrome (NS) glomeruli, with reduced Rarβ.
- Podocytes are crucial for kidney filtration and function.
Purpose of the Study:
- To investigate the specific role of podocyte Rarβ in glomerular function.
- To elucidate the impact of Rarβ deletion on kidney and liver physiology.
- To establish a mouse model for studying NS and related kidney-liver crosstalk.
Main Methods:
- Generation of a podocyte-specific Rarβ knockout mouse model (PCRB mice).
- Analysis of kidney histology, function (albuminuria, hyperfiltration), and glomerular ultrastructure.
- Genome-wide transcriptomics and proteomics of glomeruli and liver tissues.
Main Results:
- Rarβ deletion in podocytes led to NS-like symptoms: podocyte loss, foot process effacement, GBM thickening, lipid accumulation, and albuminuria.
- Increased expression of genes involved in lipid synthesis and fatty acid uptake in glomeruli.
- Unexpectedly, podocyte-specific Rarβ deletion induced hepatic steatohepatitis and systemic hyperlipidemia.
Conclusions:
- Podocyte Rarβ signaling is critical for maintaining kidney function and preventing NS.
- Kidney Rarβ plays a significant role in regulating systemic lipid metabolism and liver function.
- The PCRB mouse model effectively recapitulates key features of NS and kidney-liver crosstalk.
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