Regulation of (Pro)Renin Receptor Expression by Glucose-Induced Mitogen-Activated Protein Kinase, Nuclear Factor-κB, and Activator Protein-1 Signaling Pathways

Abstract

Renal (pro)renin receptor (PRR) expression is increased in diabetes. The exact mechanisms involved in this process are not well established. We hypothesized that high glucose up-regulates PRR through protein kinase C (PKC)-Raf-ERK and PKC-c-Jun N-terminal kinase (JNK)-c-Jun signaling pathways. Rat mesangial cells exposed to 30 mm d-glucose demonstrated significant increase in PRR mRNA and protein expression, intracellular phosphorylation of Raf-1 (Y340/341), ERK, JNK, nuclear factor-kappaB (NF-kappaB) p65 (S536) and c-Jun (S63). By chromatin immunoprecipitation assay and EMSA, high glucose induced more functional NF-kappaB and activator protein (AP)-1 dimers bound to corresponding cis-regulatory elements in the predicted PRR promoter to up-regulate PRR transcription. Conventional and novel PKC inhibitors Chelerythrine and Rottlerin, Raf-1 inhibitor GW5074, MEK1/2 inhibitor U0126, JNK inhibitor SP600125, NF-kappaB inhibitor Quinazoline, and AP-1 inhibitor Curcumin, respectively, attenuated glucose-induced PRR up-regulation. Chelerythrine and Rottlerin also inhibited glucose-induced phosphorylation of Raf-1 (Y340/341), ERK1/2, JNK, NF-kappaB p65 (S536), and c-Jun (S63). GW5074 and U0126 inhibited the phosphorylation of ERK1/2 and NF-kappaB p65 (S536). SP600125 inhibited phosphorylation of NF-kappaB p65 (S536) and c-Jun (S63). We conclude that high glucose up-regulates the expression of PRR through mechanisms dependent on both PKC-Raf-ERK and PKC-JNK-c-Jun signaling pathways. NF-kappaB and AP-1 are involved in high-glucose-induced PRR up-regulation in rat mesangial cells.

Effects of linagliptin and liraglutide on glucose- and angiotensin II-induced collagen formation and cytoskeleton degradation in cardiac fibroblasts in vitro

“…ERK1/2 and NF-κB in response to glucose and Ang II Huang et al showed that glucose increased the phosphorylation of ERK1/2, JNK and NF-κB-p65 in rat mesangial cells [13] . Glucose (25 mmol/L) has also been shown to stimulate the phosphorylation of ERK1/2 in cardiac fibroblasts [12] .…”

“…Ang II and glucose-induced collagen accumulation in the cultured cardiac fibroblasts has also been demonstrated to involve the activation of ERK1/2 and NF-κB [10,12,32] . High concentrations of glucose and Ang II can indeed activate ERK1/2 and/or NF-κB in other types of cells [13] . These previous data were confirmed in the present study in mouse cardiac fibroblasts.…”

(Pro)renin receptor: another member of the system controlled by angiotensin II?

“…First, blocking the AT1 receptor reduces the oxidative stress and NF-κB stimulation induced by high glucose because both of these effects are known to increase (P)RR expression. 24,25 Second, it has previously been demonstrated that renin suppresses (P)RR expression through the PLZF pathway. 20 Because RAS inhibitors cause a rise in renin and prorenin levels, it is possible that the increased production of renin during the AT1 receptor blockade downregulates (P)RR expression.…”

Aliskiren affects fatty-acid uptake and lipid-related genes in rodent and human cardiomyocytes

“…Increases in (P)Rr expression occur in diabetes and as a response to high glucose [78], and have also been linked to hypertension and increased heart-rate in rats [79].…”