Kidney Protein mPGES-2 Drives Renal Aging and Bone Loss in Mice

Renal aging is a major contributor to multi-organ decline in older adults, yet the molecular drivers that initiate and sustain it remain poorly understood. This study, published in Aging Cell, implicates microsomal prostaglandin E synthase-2 (mPGES-2, encoded by Ptges2) as a previously unrecognized master regulator of kidney aging and its downstream skeletal consequences.

The investigators first established that mPGES-2 protein expression rises progressively with age in both human kidney biopsies and mouse kidney tissue, with strong staining in glomerular and tubulointerstitial compartments. Global Ptges2 knockout mice aged two years displayed visibly healthier coats, improved motor performance and cognition, extended median survival, and dramatically reduced glomerulosclerosis compared to wild-type controls. Markers of kidney function—urinary albumin-to-creatinine ratio, GFR, BUN, and creatinine—were all improved, while liver enzymes remained normal, indicating systemic tolerability.

To identify which kidney cell type drives these effects, the team combined single-cell RNA sequencing with podocyte-specific and tubule-specific conditional Ptges2 knockout mouse lines. The data consistently pointed to podocytes rather than tubular cells as the dominant intrarenal source of aging-related mPGES-2 activity. Podocyte-specific deletion recapitulated the protective phenotype seen in global knockouts: reduced senescence markers (p21, p16, SA-β-gal), lower podocyte loss, and attenuated glomerular injury. Mechanistically, mPGES-2 was shown to drive podocyte senescence through a PGE2/EP1 receptor signaling axis, with EP1 antagonism phenocopying genetic deletion.

Beyond the kidney, podocyte-specific Ptges2 deletion also mitigated age-related osteoporosis. Bone microarchitectural analysis showed restored trabecular parameters, and serum levels of calcitriol (active vitamin D) and α-klotho—key renal endocrine outputs that support bone homeostasis—were significantly higher in knockout animals. These findings delineate a kidney-to-bone axis whereby podocyte mPGES-2-driven renal dysfunction impairs the endocrine signals needed for skeletal integrity.

Critically, pharmacological inhibition of mPGES-2 using the selective small-molecule inhibitor SZ0232 in aged wild-type mice reproduced the benefits of genetic deletion in both kidney and bone, without detectable adverse effects on major organs. This proof-of-concept pharmacological validation positions mPGES-2 as a tractable therapeutic target. Caveats include the reliance on mouse models, the need for human validation of the podocyte-specific mechanism, and uncertainty about optimal timing and duration of mPGES-2 inhibition in a clinical context.