Chronic treatment with lisinopril decreases proliferative and apoptotic pathways in autosomal recessive polycystic kidney disease

Guangfu Jia, Michelle Kwon, Huan Ling Liang, Jordan Mortensen, Vani Nilakantan, William E. Sweeney, Frank Park

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Angiotensin converting enzyme (ACE) inhibition is a common therapeutic modality in the treatment of autosomal recessive polycystic kidney disease (ARPKD). This study was designed to investigate whether chronic inhibition of ACE would have a therapeutic effect in attenuating the progression of renal cystogenesis in an orthologous rat model of ARPKD, the polycystic kidney (PCK) rat. Lisinopril (3 mg/kg per day) was administered orally for a period of 12 weeks, beginning at post-natal week 4. Lisinopril treatment resulted in an ∼30% improvement in the collecting duct cystic indices (CT CI) of PCK animals. Activation of extracellular signal-regulated kinase 1 (ERK1) and 2 (ERK2), proliferative signaling markers, and proliferating cell nuclear antigen (PCNA), an end-point marker for proliferation, was reduced following chronic treatment with lisinopril compared to that in vehicle-treated PCK rats. To assess whether apoptotic pathways were altered due to chronic ACE inhibition, we examined p38 mitogen activated protein kinase (MAPK) and stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK), which are markers of apoptotic signaling cascades. p38 MAPK was significantly reduced (P<0.0001) following chronic treatment with lisinopril, but no change in the activation of SAPK/JNK could be detected by immunoblot analysis. Lisinopril treatment resulted in a significant reduction (P<0.01) in cleaved caspase-7 levels, but not caspase-3 activity, in PCK rat kidneys compared to the vehicle-treated PCK rat kidneys. Proteinuria was completely ameliorated in the presence of chronic ACE inhibition in the lisinopril-treated rats compared with the vehicle-treated PCK rats. In all, these findings demonstrated that chronic ACE inhibition can beneficially alter proliferative and apoptotic pathways to promote therapeutic reductions in renal cyst development in ARPKD.

Original languageEnglish (US)
Pages (from-to)1139-1146
Number of pages8
JournalPediatric Nephrology
Volume25
Issue number6
DOIs
StatePublished - Jun 2010
Externally publishedYes

Fingerprint

Autosomal Recessive Polycystic Kidney
Lisinopril
Polycystic Kidney Diseases
Peptidyl-Dipeptidase A
Kidney
JNK Mitogen-Activated Protein Kinases
p38 Mitogen-Activated Protein Kinases
Heat-Shock Proteins
Protein Kinases
Caspase 7
Cystic Duct
Mitogen-Activated Protein Kinase 3
Mitogen-Activated Protein Kinase 1
Proliferating Cell Nuclear Antigen
Therapeutic Uses
Proteinuria
Caspase 3
Cysts

All Science Journal Classification (ASJC) codes

  • Nephrology
  • Pediatrics, Perinatology, and Child Health

Cite this

Chronic treatment with lisinopril decreases proliferative and apoptotic pathways in autosomal recessive polycystic kidney disease. / Jia, Guangfu; Kwon, Michelle; Liang, Huan Ling; Mortensen, Jordan; Nilakantan, Vani; Sweeney, William E.; Park, Frank.

In: Pediatric Nephrology, Vol. 25, No. 6, 06.2010, p. 1139-1146.

Research output: Contribution to journalArticle

Jia, Guangfu ; Kwon, Michelle ; Liang, Huan Ling ; Mortensen, Jordan ; Nilakantan, Vani ; Sweeney, William E. ; Park, Frank. / Chronic treatment with lisinopril decreases proliferative and apoptotic pathways in autosomal recessive polycystic kidney disease. In: Pediatric Nephrology. 2010 ; Vol. 25, No. 6. pp. 1139-1146.
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