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Published ahead of print on November 2, 2005
J Am Soc Nephrol 16: 3611-3622, 2005
© 2005 American Society of Nephrology
doi: 10.1681/ASN.2005020167
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Pathophysiology of Renal Disease and Progression

Activation of G{alpha}q-Coupled Signaling Pathways in Glomerular Podocytes Promotes Renal Injury

Liming Wang*, Timothy A. Fields{dagger}, Kathy Pazmino*, Qunsheng Dai§, James L. Burchette{dagger}, David N. Howell{dagger}, Thomas M. Coffman* and Robert F. Spurney*

* Division of Nephrology, Department of Medicine, {dagger} Department of Pathology, Duke University and Durham VA Medical Centers, Durham, North Carolina; and § National Institute of Environmental Health Science, National Institutes of Health, Research Triangle Park, North Carolina

Address correspondence to: Dr. Robert F. Spurney, Duke University Medical Center, Box 3014, Durham, NC 27710. Phone: 919-660-6869; Fax: 919-684-4476; E-mail: spurn002{at}mc.duke.edu

Received for publication February 18, 2005. Accepted for publication September 28, 2005.

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 (G{alpha}q). For investigating the role of G{alpha}q-coupled signaling pathways in promoting renal injury in podocytes, a constitutively active G{alpha}q subunit (G{alpha}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 G{alpha}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 G{alpha}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 G{alpha}q-coupled signaling cascades may be important effector pathways mediating renal injury.




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