Glucose promotes the production of interleukine-1beta and cyclooxygenase-2 in mesangial cells via enhanced (Pro)renin receptor expression.
(Pro)renin receptor (PRR) is present in renal glomeruli, and its expression is up-regulated in diabetes. Similarly, renal inflammation is increased in the presence of hyperglycemia. The linkage between PRR and renal inflammation is not well established. We hypothesized that glucose-induced up-regulation of PRR leads to increased production of the proinflammatory factors IL-1beta and cyclooxygenase-2 (COX-2). Studies were conducted in rat mesangial cells (RMCs) exposed to 30 mm D-glucose for 2 wk followed by PRR small interfering RNA knockdown, IL-1 receptor blockade with IL-1 receptor antagonist or angiotensin II type 1 receptor blockade with valsartan. The results showed that D-glucose treatment up-regulates prorenin, renin, angiotensin II, PRR, IL-1beta, and COX-2 mRNA and protein expression and increases phosphorylation of ERK1/2, c-Jun N-terminal kinase, c-Jun, and nuclear factor-kappaB (NF-kappaB) p65 (serine 276,468 and 536), respectively. PRR small interfering RNA attenuated PRR, IL-1beta, and COX-2 mRNA and protein expressions and significantly decreased angiotensin II production and phosphorylation of ERK1/2 and NF-kappaB p65 associated with high glucose exposure. Similarly, IL-1 receptor antagonist significantly reduced COX-2 mRNA and protein expression induced by high glucose. COX-2 inhibition reduced high-glucose-induced PRR expression. We conclude that glucose induces the up-regulation of PRR and its ligands prorenin and renin, leading to increased IL-1beta and COX-2 production via the angiotensin II-dependent pathway. It is also possible that PRR could enhance the production of these inflammatory cytokines through direct stimulation of ERK1/2-NF-kappaB signaling cascade.
Huang
Jiqian
J
Department of Medicine, University of Virginia Health System, Charlottesville, Virginia 22908-1409, USA.
Siragy
Helmy M
HM
D000804:Angiotensin II / Q000378:metabolism; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005947:Glucose / Q000494:pharmacology*; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism*; D050527:Mesangial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D034622:RNA Interference; D051381:Rats; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D012083:Renin / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013777:Tetrazoles / Q000494:pharmacology; D013997:Time Factors; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism; D014633:Valine / Q000031:analogs & derivatives / Q000494:pharmacology; D000068756:Valsartan; D000093342:Prorenin Receptor
D047228:Angiotensin II Type 1 Receptor Blockers; D053583:Interleukin-1beta; D011956:Receptors, Cell Surface; D013777:Tetrazoles; D051996:Transcription Factor RelA; D000804:Angiotensin II; D000068756:Valsartan; D051546:Cyclooxygenase 2; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D012083:Renin; D014633:Valine; D005947:Glucose; D000093342:Prorenin Receptor