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Abstract: TH-PO985

Chronic High-Dose Candesartan Therapy Promotes Podocyte Recruitment from Glomerular Parietal Epithelial Cells Involving Suppression of GSK3β Signaling

Session Information

Category: Pathology and Lab Medicine

  • 1501 Pathology and Lab Medicine: Basic


  • Lu, Minglei, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
  • Dworkin, Lance D., University of Toledo Medical Center, Toledo, Ohio, United States
  • Liu, Zhangsuo, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
  • Gong, Rujun, University of Toledo Medical Center, Toledo, Ohio, United States

Evidence suggests that non-podocyte cells like glomerular parietal epithelial cells(PEC) contribute to podocyte repopulation and glomerular filtration barrier(GFB) repair in chronic kidney disease(CKD). Angiotensin blockades, as the standard of care for CKD, however, only exhibit a marginal effect on podocyte regeneration. At doses higher than recommended, angiotensin blockades are known to exert an extra anti-proteinuric and renoprotective effect. This study aims to explore if this additional benefit is associated with podocyte regeneration.


After unilateral nephrectomy, spontaneously hypertensive rats received variable doses (standard, 5 mg/kg/d; high, 25 mg/kg/d; and ultrahigh, 75 mg/kg/d) of candesartan for 14 months. Renal expression of podocyte and PEC markers was evaluated.


Despite a comparable effect attained by all doses on normalizing systemic hypertension, high and ultrahigh dose candesartan exhibited a more potent proteinuria-reducing effect that is independent of blood pressure control. Accordingly, glomerulosclerosis was improved by candesartan in a dose dependent mode. The variable outcomes in proteinuria is suggestive of disparity in GFB integrity. Indeed, increasing doses of candesartan progressively augmented the number of podocytes, marked by WT-1 staining. This effect seems to be attributable to new podocyte recruitment from PEC, because the number of cells in glomerular tufts positive for both synaptopodin and Pax2, a PEC marker, was increased. This coincided with a potentiated transdifferentiation of PEC to podocyte phenotypes in parietal epithelia. In contrast, PEC activation, probed by CD44 expression in glomeruli, was diminished by candesartan in a dose dependent fashion. Glycogen synthase kinase (GSK)3β, a multitasking serine/threonine protein kinase, has been recently implicated in impaired podocyte regeneration. In the diseased kidney, glomerular expression of GSK3β was amplified, predominantly located to PEC and podocytes. Increasing dose of candesartan progressively obliterated glomerular overexpression of GSK3β, concomitant with an improved glomerular histology and podocyte integrity.


Chronic high-dosage candesartan therapy is able to potentiate podocyte derivation from PEC via inhibition of GSK3β signaling and attenuate glomerular injury.


  • NIDDK Support