Interconnected Network Motifs Control Podocyte Morphology and Kidney Function

Abstract

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.

Renal injury in Seipin ‐deficient lipodystrophic mice and its reversal by adipose tissue transplantation or leptin administration alone: adipose tissue‐kidney crosstalk

“…Briefly, the kidneys from anesthetized WT mice were removed, minced, digested, and then passed through a graded series of stainless steel sieves; glomerular cores remaining on the finest sieve were collected. The purity of glomeruli was verified under microscopy to be .90% (23). The glomeruli were then used for RNA isolation, and Seipin expression was detected by real-time PCR.…”

Prostaglandin I2 Receptor Agonism Preserves β-Cell Function and Attenuates Albuminuria Through Nephrin-Dependent Mechanisms

“…PGI 2 is a cyclooxygenase-derived prostanoid that exerts its cellspecific effects through both IP receptor-dependent and IP receptor-independent pathways. The IP receptor signals predominantly through 39,59-cyclic adenosine monophosphate (cAMP)-dependent protein kinase A (PKA) activation (12), a pivotal regulator of the podocyte differentiated state (13). In the current study, we hypothesized that IP receptor-mediated PKA activation would augment nephrin phosphorylation, and by taking advantage of a recently developed first-in-class IP receptor agonist MRE-269 (and its prodrug form selexipag) (14-16), we explored these effects in pancreatic b-cells and in podocytes.…”

Advances in slit diaphragm signaling

“…In addition to the imaging advancements described above, these studies have defined podocyte-specific gene splicing patterns [91], produced a computationally defined signature to evaluate how diseases affect the podocyte [92], contributed to a growing list of urinary biomarkers for podocyte injury [93][94][95][96] and generated a comprehensive podocyte protein-protein interaction network [97] -leading to the characterization of several novel podocyte proteins [98,99]. Further, the application of systems biology methods to the podocyte has enormous potential in the pursuit of personalized medicine in nephrology, wherein we can better predict the effects of therapeutic combinations and suggest patient-specific drug intervention strategies [100].…”