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

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 approximately 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.

Apoptosis in Polycystic Kidney Disease: From Pathogenesis to Treatment

“…The GlcCer synthase inhibitor, Genz-123346, also slowed cyst growth by decreasing the proliferation and apoptosis in jck mice (120). The angiotensin converting enzyme inhibitor, Lisinopril (121), and water intake (65) have been reported to delay cyst growth associated with the decreased proliferation and apoptosis in the PCK rat. The studies in Han:SPRD rats also suggest that inhibiting proliferation and apoptosis with the caspase inhibitor IDN-8050 (75), soy protein feed (122), catechol-O-methyltransferase (COMT) inhibitor Tolcapone (123) and 2-hydroxyestradiol (124) can slow the cyst expansion.…”

“…In the PCK rat, apoptotic cells are commonly found in the normal tubules and dilated tubules, but are less observed in cysts lined by flat epithelium (64). Apoptosis in the PCK rat may be mediated by p38 mitogen activated protein kinase (MAPK) signaling and caspase-7 but not caspase-3 (65).…”

Biology of Cilia and Ciliopathies

“…Roscovitine, currently used in cancer treatment because it inhibits cell cycle, show positive effects in PKD models [146]. Lisinopril, an inhibitor of angiotensin converting enzyme (ACE) also alters proliferative and apoptotic pathways, reducing cyst development [147]. Patients with PKD show high levels of circulating vasopressin.…”

Novel Therapies for Polycystic Kidney Disease

“…In the PCK rat, an orthologous model of ARPKD, liver over-expresses ACE and has increased AII which was thought to be secondary to the increased TGF-β expression [87]. When PCK rats were treated with lisinopril, the proliferation, apoptosis and renal pathology was ameliorated with the elimination of the model's proteinuria [88]. The current HALT PKD study supported by the NIH (Table 1) is comparing the affects of an ACE inhibitor alone or in combination with an ARB in patients with ADPKD.…”