ERRγ deletion in podocytes accelerates aging related kidney disease

Area of Science:

• Nephrology and Molecular Biology
• Mitochondrial Biology and Aging

Background:

• Aging kidneys exhibit increased urinary albumin, decreased podocyte density, impaired mitochondrial function, and inflammation.
• Previous studies showed a pan-ERR agonist reversed these age-related kidney changes.
• The roles of individual ERR isoforms, particularly ERRγ in aging podocytes, remain unclear.

Purpose of the Study:

• To investigate the specific role of Estrogen-Related Receptor gamma (ERRγ) in aging podocytes.
• To determine if podocyte-specific deletion of ERRγ exacerbates age-related kidney dysfunction.

Main Methods:

• Generated podocyte-specific ERRγ knockout mice by crossing ERRγ floxed mice with podocin-Cre mice.
• Assessed kidney function (albuminuria, podocyte density) and kidney tissue morphology via Electron Microscopy (EM).
• Analyzed mitochondrial function using Fluorescence Lifetime Imaging Microscopy (FLIM) to measure NADH and FAD lifetimes.

Main Results:

• Aged mice with podocyte-specific ERRγ deletion showed increased albuminuria and decreased podocyte density compared to wild-type.
• Deletion of ERRγ reduced expression of PGC-1α, CPT1a, and MCAD, impacting mitochondrial biogenesis and fatty acid oxidation.
• EM revealed glomerular basement membrane thickening, podocyte foot process effacement, and severe mitochondrial damage.
• FLIM indicated a metabolic shift towards glycolysis and reduced mitochondrial redox capacity.

Conclusions:

• Podocyte-specific deletion of ERRγ accelerates age-related kidney disease.
• ERRγ plays a crucial role in maintaining podocyte mitochondrial function and integrity.
• ERRα and ERRγ may act synergistically to regulate mitochondrial function and prevent age-related kidney disease.