Activation of Galpha q-coupled signaling pathways in glomerular podocytes promotes renal injury.
The glomerular podocyte plays a key role in maintaining the integrity of the glomerular filtration barrier. This function may be regulated by activation of cell surface G protein-coupled receptors (GPCR). Studies suggest that podocytes express GPCR that are implicated in the pathogenesis of glomerular diseases. Common to these GPCR systems is activation of phospholipase C through the Gq alpha-subunit (Galpha q). For investigating the role of Galpha q-coupled signaling pathways in promoting renal injury in podocytes, a constitutively active Galpha q subunit (Galpha qQ > L) was expressed in glomerular podocytes using the mouse nephrin promoter. Transgenic (TG) mice demonstrated albuminuria as well as a decrease in both kidney mass and nephron number. By light microscopy, a portion of the TG mice had glomerular abnormalities, including focal to diffuse hypercellularity and segmental sclerosis. Consistent with injury-promoting effects of Galpha qQ > L, there was a significant reduction in podocalyxin mRNA as well as nephrin mRNA and protein levels in glomeruli from TG mice compared with non-TG controls. Expression of the transgene also seemed to increase susceptibility to glomerular injury, because treatment with puromycin aminonucleoside enhanced proteinuria in TG mice compared with non-TG littermate controls (4.2 +/- 1.0 [TG] versus 1.6 +/- 0.3 [non-TG] mg/24 h; P = 0.0161). Thus, activation of Galpha q in glomerular podocytes caused alterations in glomerular histomorphology, albuminuria, decreased nephron mass, and reduced glomerular expression of both nephrin and podocalyxin as well as enhanced susceptibility to glomerular damage induced by puromycin aminonucleoside. It is speculated that Galpha q-coupled signaling cascades may be important effector pathways mediating renal injury.
Wang
Liming
L
Division of Nephrology, Department of Medicine, Duke University and Durham VA Medical Centers, Durham, NC 27710, USA.
Fields
Timothy A
TA
Pazmino
Kathy
K
Dai
Qunsheng
Q
Burchette
James L
JL
Howell
David N
DN
Coffman
Thomas M
TM
Spurney
Robert F
RF
D000419:Albuminuria / Q000503:physiopathology; D000818:Animals; D001483:Base Sequence; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005260:Female; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000235:genetics / Q000502:physiology*; D005919:Glomerular Filtration Rate; D015151:Immunoblotting; D007674:Kidney Diseases / Q000235:genetics / Q000473:pathology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D050199:Podocytes / Q000166:cytology* / Q000378:metabolism; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000235:genetics; D012720:Severity of Illness Index; D015398:Signal Transduction; D015854:Up-Regulation
D012333:RNA, Messenger; D019206:GTP-Binding Protein alpha Subunits, Gi-Go