Rosiglitazone Inhibits Angiotensin II-Induced Proliferation of Glomerular Mesangial Cells via the Gαq/Plcβ4/TRPC Signaling Pathway

Abstract

Background/Aims: Mesangial cell proliferation and extracellular matrix accumulation (ECM) deposition play an important role in the pathogenesis of glomerulosclerosis. TRPC and PPAR-γ can regulate cell proliferation. Angiotensin II (AngII) can induce mesangial cell proliferation and affect TRPC expression. However, the mechanism has not been fully elucidated. This study was designed to investigate the role of TRPC and the effect of rosiglitazone (RSG) in the proliferation of rat glomerular mesangial cells (HBZY-1) that were stimulated by AngII and the underlying mechanisms. Methods: Immunofluorescence staining and qRT-PCR were performed to examine the expression levels of TRPCs in HBZY-1. Gene expression levels of TRPC, PPAR-γ, RGS4 (regulators of G protein signaling), the GPCR/Gαq/PLCβ4/TRPC signaling pathway and major downstream molecules (PCNA, SKP2, P21 and P27) were detected by qRT-PCR and western blotting. Additionally, changes in intracellular Ca²⁺ levels were determined through Fluo-4 Ca²⁺ imaging, and the cell cycle was analyzed by flow cytometry. Results: Our results found that TRPC1 and 6 were at higher expression levels in HBZY-1 cells. Following AngII stimulation, there were increased levels of TRPC1 and 6, Ca²⁺ entry, PCNA and SKP2, decreased expression levels of P21 and P27 and a reduced G₀/G₁ percentage. Silencing TRPC1 and 6 by siRNAs led to decrease in Ca²⁺ influx, G₀/G₁ cell cycle arrest and cell proliferation. Notably, PPAR-γ activation by RSG upregulated RGS4 expression, which can interact with the Gαq family to inhibit the Gαq-mediated signaling cascade. The results were similar to silencing TRPC1 and 6 by siRNAs. Conclusion: All these results indicate that RSG could inhibit HBZY-1 cell proliferation via the Gαq/PLCβ4/TRPC signaling pathway.

TRPC channels: Structure, function, regulation and recent advances in small molecular probes

“…Here, the drug was thought to activate PPAR-γ, which upregulates RGS4 expression and in turn reduces G q signaling. The decreased G q activity then results in lower activation of TRPC1 and TRPC6 by Ang II (Wei et al, 2017). Also acting through PPAR-γ, the protein kinase G activator, sildenafil, was shown to prevent proteinuria through suppressing the increase in the podocyte expression of TRPC6 in rats with nephropathy induced by adriamycin and mice suffering from renal injury due to hyperglycemia.…”

Extracellular Matrix in Secondary Palate Development

“…Expectedly, proteins involved in pathways regulating cell migration and rearrangement play an important role and mutations in their genes result in cleft palate as seen with the Rho‐GTPase‐activating protein ( ARHGAP29 , 610496) or the calcium/calmodulin‐dependent serine protein kinase ( CASK , 300749) (Volta et al, ; Jiang et al, ; Qiao et al, ). It is also tempting to include other signaling molecules, although not necessarily linked to the same migratory or morphological functions, as seen with the phospholipase β4 (Auriculocondylar syndrome 2, 614669) and Yes‐associated protein 1 (Coloboma with or without cleft palate, 120433) (Qiao et al, ; Sabra et al, ; Wei et al, ). Thus, it appears that the coordination of cellular activities, like migration, requires the integration of cell responses from the cell surface connected to the ECM to the cytoskeleton and nucleus.…”

PPARγ and TGFβ—Major Regulators of Metabolism, Inflammation, and Fibrosis in the Lungs and Kidneys

“…Apart from the damaged podocytes, glomerular mesangial cells also play pivotal role in the pathogenesis of glomerular sclerosis and function loss. PPARγ activation in cultured rat glomerular mesangial cells decreased AngII-induced Ca 2+ influx via reducing TRPC activity, inhibiting mesangial cell proliferation, one of the hallmarks of glomerulosclerosis [ 75 ].…”