Interconnected network motifs control podocyte morphology and kidney function.
Podocytes are kidney cells with specialized morphology that is required for glomerular filtration. Diseases, such as diabetes, or drug exposure that causes disruption of the podocyte foot process morphology results in kidney pathophysiology. Proteomic analysis of glomeruli isolated from rats with puromycin-induced kidney disease and control rats indicated that protein kinase A (PKA), which is activated by adenosine 3',5'-monophosphate (cAMP), is a key regulator of podocyte morphology and function. In podocytes, cAMP signaling activates cAMP response element-binding protein (CREB) to enhance expression of the gene encoding a differentiation marker, synaptopodin, a protein that associates with actin and promotes its bundling. We constructed and experimentally verified a β-adrenergic receptor-driven network with multiple feedback and feedforward motifs that controls CREB activity. To determine how the motifs interacted to regulate gene expression, we mapped multicompartment dynamical models, including information about protein subcellular localization, onto the network topology using Petri net formalisms. These computational analyses indicated that the juxtaposition of multiple feedback and feedforward motifs enabled the prolonged CREB activation necessary for synaptopodin expression and actin bundling. Drug-induced modulation of these motifs in diseased rats led to recovery of normal morphology and physiological function in vivo. Thus, analysis of regulatory motifs using network dynamics can provide insights into pathophysiology that enable predictions for drug intervention strategies to treat kidney disease.
1Department of Pharmacology and Systems Therapeutics, Mount Sinai School of Medicine, New York, NY 10029, USA.
Evren U
EU
Azeloglu
Simon V
SV
Hardy
Narat John
NJ
Eungdamrong
Yibang
Y
Chen
Gomathi
G
Jayaraman
Peter Y
PY
Chuang
Wei
W
Fang
Huabao
H
Xiong
Susana R
SR
Neves
Mohit R
MR
Jain
Hong
H
Li
Avi
A
Ma'ayan
Ronald E
RE
Gordon
John Cijiang
JC
He
Ravi
R
Iyengar
D000818:Animals; D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D015870:Gene Expression; D053263:Gene Regulatory Networks; D015151:Immunoblotting; D007668:Kidney / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D007674:Kidney Diseases / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism; D008854:Microscopy, Electron; D050199:Podocytes / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D040901:Proteomics / Q000379:methods; D011691:Puromycin; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction
D017362:Cyclic AMP Response Element-Binding Protein; D008565:Membrane Proteins; D008840:Microfilament Proteins; C503968:Synpo protein, mouse; C113267:nephrin; D011691:Puromycin; D017868:Cyclic AMP-Dependent Protein Kinases