Podocyte mPGES-2 Determines Renal Aging and Contributes to Senile Osteoporosis

Area of Science:

• Gerontology
• Nephrology
• Endocrinology

Background:

• Renal aging contributes to systemic health decline, but its molecular mechanisms are not fully understood.
• Microsomal prostaglandin E synthase-2 (mPGES-2) is implicated in inflammatory processes, but its role in kidney aging is unclear.

Purpose of the Study:

• To investigate the role of mPGES-2 in renal aging and its associated skeletal consequences.
• To identify the specific kidney cell type where mPGES-2 exerts its effects on aging.

Main Methods:

• Genetic ablation of Ptges2 in mice to assess its impact on aging phenotypes.
• Single-cell transcriptomics and cell-specific knockout models (podocyte and tubule) to pinpoint mPGES-2's cellular origin of action.
• Pharmacological inhibition of mPGES-2 using SZ0232 in aged mice.

Main Results:

• Genetic deletion of Ptges2 improved health indices, survival, and alleviated kidney aging markers like glomerulosclerosis and podocyte senescence.
• Podocyte-specific mPGES-2 deficiency, not tubular, was identified as the primary driver of kidney aging.
• mPGES-2 promotes podocyte senescence via a prostaglandin E2 (PGE2)/EP1 signaling pathway, impacting renal calcitriol and α-klotho levels, thus affecting bone health.
• Pharmacological inhibition of mPGES-2 with SZ0232 mimicked genetic benefits, reducing renal aging and improving bone microarchitecture without adverse effects.

Conclusions:

• Podocyte mPGES-2 is a key regulator of kidney aging and its skeletal complications.
• Targeting mPGES-2, particularly in podocytes, represents a promising therapeutic strategy for age-related kidney disease and osteoporosis.