Extracellular Signal–Regulated Kinase Inhibition Slows Disease Progression in Mice with Polycystic Kidney Disease

Abstract

The expression of mitogen-activated protein kinases (MAPK) in DBA/2-pcy/pcy (pcy) mice, a murine model of polycystic kidney disease was investigated. Proliferating cell nuclear antigen-positive cells were recognized in cyst epithelium from embryonic day 14.5 to 25 wk of age. Extracellular signal-regulated kinase (ERK) was expressed in the renal tubules of control and pcy mice, but stronger immunostaining was observed in cyst epithelium. Phosphorylated ERK was detected only in pcy mice and was localized predominantly in the cysts. p38 MAPK (p38) was no longer expressed after birth in controls but was detected in the cyst epithelium and in occasional tubular cells of pcy mice at all stages examined. c-Jun N-terminal kinase (JNK) was expressed in all tubular segments of controls after neonatal day 7, whereas in pcy kidneys, tubules became positive for JNK after 8 wk, and the cysts expressed little JNK. Administration of an oral MAP/ERK kinase inhibitor, PD184352, 400 mg/kg per d, to 10-wk-old pcy mice daily for the first week and then every third day for 6 additional weeks significantly decreased BP, kidney weight, serum creatinine level, and water intake and significantly increased urine osmolality. The cystic index and expression of phosphorylated ERK and ERK were significantly lower in PD184352-treated pcy mice. These results demonstrate that the expression of MAPK is dysregulated in cyst epithelium and that inhibition of ERK slowed the progression of renal disease in pcy mice.

Proximal Tubule Proliferation Is Insufficient to Induce Rapid Cyst Formation after Cilia Disruption

“…7 The possible association between cyst formation and proliferation is further supported by data showing decreased proliferation rates in the kidney coincide with a decrease in cyst formation. 26,27 Proliferation as the basis of cyst initiation in cilia mutants is attractive based on the role of ciliary proteins in regulating mitosis and oriented cell division. 12 In several cystic kidney models, the orientation of cell division is random rather than occurring along the longitudinal axis of the nephron as seen in normal animals.…”

Cdc42 Deficiency Causes Ciliary Abnormalities and Cystic Kidneys

“…41 MAPK activation, specifically phosphorylation of the final protein ERK (pERK) in this pathway, was found to be significantly elevated by Western blot in three of five mice examined ( Figure 9A). Importantly, in tissue sections, by immunohistochemistry, pERK was increased in kidney cyst cells in all five Cdc42 kidney-specific knockout mice examined ( Figure 9B and Supplemental Figure 2).…”

Targeting of Receptor for Advanced Glycation End Products Suppresses Cyst Growth in Polycystic Kidney Disease

“…6B, Con Ad, 17.81 Ϯ 4.8; RAGE Ad, 10.5 Ϯ 2.2). Activation of MAPK/ERK is important for cyst enlargement in PKD and is a cell proliferation marker in PKD (31,32). Next, we conducted immunostaining and Western blot analyses to evaluate ERK phosphorylation more precisely.…”