An information theoretic approach to insulin sensing by human kidney podocytes. (1st December 2020)

• Record Type: Journal Article
• Authors: Pope, Robert JP.; Garner, Kathryn L.; Voliotis, Margaritis; Lay, Abigail C.; Betin, Virginie MS.; Tsaneva-Atanasova, Krasimira; Welsh, Gavin I.; Coward, Richard JM.; McArdle, Craig A.
• Is Part Of: Molecular and cellular endocrinology. Volume 518(2020)
• Publication Date: 2020-12-01
• Subjects: Insulin receptor -- Podocyte -- Diabetes -- Phosphatidyl-inositol 3 kinase (PI3K) -- Mutual information -- Cell signaling; Endocrinology -- Periodicals; Molecular biology -- Periodicals; Cytology -- Periodicals; Endocrinology -- Periodicals; Hormones -- Periodicals; Endocrinologie -- Périodiques; Cytology; Endocrinology; Molecular biology; Periodicals; 573.4
• DOI: 10.1016/j.mce.2020.110976
• Languages: English
• ISSNs: 0303-7207

Abstract

Abstract: Podocytes are key components of the glomerular filtration barrier (GFB). They are insulin-responsive but can become insulin-resistant, causing features of the leading global cause of kidney failure, diabetic nephropathy. Insulin acts via insulin receptors to control activities fundamental to GFB integrity, but the amount of information transferred is unknown. Here we measure this in human podocytes, using information theory-derived statistics that take into account cell-cell variability. High content imaging was used to measure insulin effects on Akt, FOXO and ERK. Mutual Information (MI) and Channel Capacity (CC) were calculated as measures of information transfer. We find that insulin acts via noisy communication channels with more information flow to Akt than to ERK. Information flow estimates were increased by consideration of joint sensing (ERK and Akt) and response trajectory (live cell imaging of FOXO1-clover translocation). Nevertheless, MI values were always <1Bit as most information was lost through signaling. Constitutive PI3K activity is a predominant feature of the system that restricts the proportion of CC engaged by insulin. Negative feedback from Akt supressed this activity and thereby improved insulin sensing, whereas sensing was robust to manipulation of feedforward signaling by inhibiting PI3K, PTEN or PTP1B. The decisions made by individual podocytes dictate GFB integrity, so we suggest that understanding the information on which the decisions are based will improve understanding of diabetic kidney disease and its treatment. Graphical abstract: Image 1 Highlights: Podocytes are insulin-responsive and insulin-resistance causes kidney disease with features of diabetic nephropathy. Information theory-derived statistics can measure information flow in cells, providing a novel approach to insulin sensing. In insulin-stimulated human podocytes most information is lost through signaling but it is protected by trajectory sensing. It is also protected by dual sensing, robust to manipulating forward signaling and sensitive to negative feedback inhibition. Knowing how system features influence information transfer may help understanding of kidney disease and inform its treatment.