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miR-135a-5p Is a Promising Target to Prevent the Glomerulosclerosis Associated with Podocyte Developmental Toxicity

Xiaoqi Zhao1,2, Haiyun Chen1, Yanan Zhu3

  • 1Department of Pharmacology, Wuhan University School of Basic Medical Sciences, Wuhan, Hubei, China.

Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
|January 30, 2026
PubMed

Insights

Prenatal dexamethasone exposure (PDE) programs offspring for chronic kidney disease by disrupting podocyte development via an epigenetic pathway involving miR-135a-5p and KLF4. Targeting miR-135a-5p may prevent this fetal-origin glomerulosclerosis.

Area of Science:

  • Nephrology
  • Developmental Biology
  • Epigenetics

Background:

  • Podocyte developmental defects initiate glomerulosclerosis.
  • Prenatal dexamethasone exposure (PDE) may predispose offspring to chronic kidney disease via unknown mechanisms.
  • Understanding the fetal programming of kidney disease is crucial.

Purpose of the Study:

  • To elucidate the mechanisms by which PDE induces glomerulosclerosis in offspring.
  • To identify the role of epigenetic modifications in PDE-induced podocyte injury.
  • To explore miR-135a-5p as a therapeutic target for preventing fetal-origin glomerulosclerosis.

Main Methods:

  • Investigated PDE effects on podocyte differentiation and glomerulosclerosis in adult rat offspring.
  • Analyzed KLF4 and miR-135a-5p expression in differentiating stem cells exposed to dexamethasone.
  • Utilized chromatin immunoprecipitation and reporter assays to examine glucocorticoid receptor (GR) binding and epigenetic modifications at the miR-135a-5p promoter.
  • Administered a miR-135a-5p antagomir to assess its therapeutic potential.

Main Results:

  • PDE disrupted podocyte differentiation and caused glomerulosclerosis in adult rats.
  • PDE downregulated KLF4 and upregulated miR-135a-5p, a validated target of miR-135a-5p.
  • Activated GR bound the miR-135a-5p promoter, recruiting P300 to enhance histone acetylation and sustain miR-135a-5p upregulation.
  • Elevated miR-135a-5p suppressed KLF4, impairing podocyte development and promoting glomerular injury.
  • miR-135a-5p antagomir administration partially restored podocyte markers and ameliorated glomerulosclerosis.

Conclusions:

  • Identified a novel GR-P300-miR-135a-5p/KLF4 epigenetic axis in PDE-induced fetal programming of podocyte injury.
  • Mechanistic insight into developmental origins of glucocorticoid-induced kidney disease.
  • miR-135a-5p is a potential biomarker and therapeutic target for preventing fetal-origin glomerulosclerosis.

Keywords:
developmental toxicityepigeneticmiRNA therapypodocyteprenatal dexamethasone exposurerenal disease

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