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

  • Aging Cell. 2026 Jul;25(7):e70609. doi: 10.1111/acel.70609.
Dandan Zhong  1  2 ,  Chang Hao  1  2  3 ,  Mengyue Li  1  2 ,  Jing Liu  1  2 ,  Zheng Xu  4 ,  Jianteng Zhou  5 ,  Lu Zhao  1  2 ,  Siyu Ni  1  2  6 ,  Zhenchao Hu  1  2 ,  Yue Sun  1  2 ,  Yingying Zou  1  2 ,  Dong Sun  7  8 ,  Hao Guo  9 ,  Zhanjun Jia  6 ,  Dong Guo  1  2 ,  Jun-Li Cao  4 ,  Ying Sun  1  2
Affiliations
  • 1. Jiangsu Key Laboratory of Geriatric Precision Medicine and Aging Intervention, Xuzhou Medical University, Xuzhou, Jiangsu, China.
  • 2. Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, Jiangsu, China.
  • 3. Taicang Loujiang New Town Hospital, Suzhou, Jiangsu, China.
  • 4. Jiangsu Province Key Laboratory of Anesthesiology & Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology & NMPA Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, Xuzhou Medical University, Xuzhou, Jiangsu, China.
  • 5. Jiangsu Engineering Center for Precision Diagnosis and Treatment Research of Polygenic Diseases, Key Laboratory of Genetic Foundation and Clinical Application, Department of Genetics, Xuzhou Medical University, Xuzhou, China.
  • 6. Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, Nanjing, Jiangsu, China.
  • 7. Department of Nephrology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China.
  • 8. Clinical Research Center for Kidney Disease, Xuzhou Medical University, Xuzhou, Jiangsu, China.
  • 9. Department of Science and Technology, Xuzhou Medical University, Xuzhou, Jiangsu, China.
PMID: 42347750 DOI: 10.1111/acel.70609
Abstract

Renal aging shortens healthspan and propagates organ dysfunction beyond the kidney, yet its molecular drivers remain incompletely defined. Here we identify microsomal prostaglandin E synthase-2 (mPGES-2) as a critical regulator of renal aging and its skeletal consequence. Genetic ablation of Ptges2 improved health indices in aged mice, prolonged median survival, and markedly alleviated glomerulosclerosis, podocyte injury, and renal senescence. Single-cell transcriptomic analysis, together with podocyte- and tubule-specific knockout models, showed that podocyte mPGES-2, rather than tubular mPGES-2, is the dominant intrarenal driver of aging-related kidney injury. Mechanistically, mPGES-2 promoted podocyte senescence through a PGE2/EP1 signaling axis. Podocyte-specific Ptges2 deletion also mitigated age-related osteoporosis and restored renal calcitriol and α-klotho, supporting a kidney-bone mechanism secondary to impaired renal endocrine function. Consistent with the genetic models, pharmacological inhibition of mPGES-2 with SZ0232 attenuated renal aging and improved bone microarchitecture in aged mice. Both genetic deficiency and pharmacological inhibition of mPGES-2 were well tolerated, with no overt adverse effects on major organs. These findings identify podocyte mPGES-2 as a druggable determinant of renal aging and a potential therapeutic target for aging-associated osteoporosis.

Keywords
kidney–bone axis; mPGES‐2; osteoporosis; podocyte; renal aging.
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