Multistep Virtual Screening Based Identification of Homeodomain-Interacting Protein Kinase 2 Inhibitors: An Opportunity for Treating Chronic Kidney Disease

Insulin resistance is a common finding in chronic kidney disease (CKD) and is manifested by mild fasting hyperglycemia and abnormal glucose tolerance testing. Circulating levels of glucocorticoids are high. In muscle, changes in the insulin signaling pathway occur. An increase in the regulatory p85 subunit of Class I phosphatidylinositol 3-Kinase enzyme leads to decreased activation of the downstream effector protein kinase B (Akt). Mechanisms promoting muscle proteolysis and atrophy are unleashed. The link of Akt to the ubiquitin proteasome pathway, a major degradation pathway in muscle, is discussed. Another factor associated with insulin resistance in CKD is angiotensin II (Ang II) which appears to induce its intracellular effects through inflammatory cytokines or reactive oxygen species. Skeletal muscle ATP is depleted and the ability of AMP-activated protein kinase (AMPK) to replenish energy stores is blocked. How this can be reversed is discussed. Interleukin-6 (IL-6) levels are elevated in CKD and impair insulin signaling at the level of IRS-1. With exercise, IL-6 levels are reduced; glucose uptake and utilization are increased. For patients with CKD, exercise may improve insulin signaling and build up muscle. Treatment strategies for preventing muscle atrophy are discussed.

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Redox and Activation of Protein Kinase A Dysregulates Calcium Homeostasis in Pulmonary Vein Cardiomyocytes of Chronic Kidney Disease

Journal of the American Heart Association ◽

10.1161/jaha.117.005701 ◽

2017 ◽

Vol 6 (7) ◽

Cited By ~ 5

Author(s):

Shih‐Yu Huang ◽

Yao‐Chang Chen ◽

Yu‐Hsun Kao ◽

Ming‐Hsiung Hsieh ◽

Yung‐Kuo Lin ◽

...

Keyword(s):

Chronic Kidney Disease ◽

Protein Kinase ◽

Kidney Disease ◽

Protein Kinase A ◽

Pulmonary Vein ◽

Calcium Homeostasis ◽

Kinase A

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Vasopressin Induces Urinary Uromodulin Secretion By Activating PKA (Protein Kinase A)

Hypertension ◽

10.1161/hypertensionaha.121.17127 ◽

2021 ◽

Author(s):

Azuma Nanamatsu ◽

Takayasu Mori ◽

Fumiaki Ando ◽

Taisuke Furusho ◽

Shintaro Mandai ◽

...

Keyword(s):

Chronic Kidney Disease ◽

Urinary Tract ◽

Protein Kinase ◽

Kidney Disease ◽

Protein Kinase A ◽

Urinary Tract Infections ◽

Kidney Stones ◽

Camp Signaling ◽

Tract Infections ◽

Kinase A

Urinary uromodulin, secreted by renal tubular cells, protects against urinary tract infections and kidney stones. In contrast, the intracellular accumulation of uromodulin is associated with hypertension and chronic kidney disease. However, the physiological stimuli for urinary uromodulin secretion remain largely unknown. Here, we showed that desmopressin, a vasopressin type 2 receptor agonist, dramatically increased short-term tubular uromodulin secretion in mice. Immunofluorescence studies and ultracentrifugation-based polymerization assay suggested that desmopressin induced intraluminal polymeric filaments of uromodulin, indicating physiologically functional secretion. As a result of increased excretion, uromodulin abundance in the murine kidney was clearly reduced by desmopressin. We investigated kidney epithelial cells stably expressing uromodulin to clarify the molecular mechanism. Apical uromodulin secretion was clearly increased in response to vasopressin/cAMP signaling, consistent with in vivo experiments. We also demonstrated that the response was dependent on epithelial cell polarity and cyclic AMP-dependent PKA (protein kinase A) signaling pathway. cAMP-mediated activation of proteases was suggested to be involved. In contrast, basolateral secretion of uromodulin was independent of cAMP signaling. Our work revealed vasopressin/cAMP/PKA signaling as a physiological stimulus of urinary uromodulin secretion. This finding may provide the basis for novel treatment strategies for urinary tract infections, kidney stones, and potentially hypertension and chronic kidney disease.

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Early signalling events of autophagy

Essays in Biochemistry ◽

10.1042/bse0550001 ◽

2013 ◽

Vol 55 ◽

pp. 1-15 ◽

Cited By ~ 16

Author(s):

Laura E. Gallagher ◽

Edmond Y.W. Chan

Keyword(s):

Protein Kinase ◽

Focal Adhesion Kinase ◽

Focal Adhesion ◽

Mammalian Cells ◽

Mammalian Target Of Rapamycin ◽

Interacting Protein ◽

The Core ◽

Autophagy Gene ◽

Autophagy Induction ◽

Cellular Pathways

Autophagy is a conserved cellular degradative process important for cellular homoeostasis and survival. An early committal step during the initiation of autophagy requires the actions of a protein kinase called ATG1 (autophagy gene 1). In mammalian cells, ATG1 is represented by ULK1 (uncoordinated-51-like kinase 1), which relies on its essential regulatory cofactors mATG13, FIP200 (focal adhesion kinase family-interacting protein 200 kDa) and ATG101. Much evidence indicates that mTORC1 [mechanistic (also known as mammalian) target of rapamycin complex 1] signals downstream to the ULK1 complex to negatively regulate autophagy. In this chapter, we discuss our understanding on how the mTORC1–ULK1 signalling axis drives the initial steps of autophagy induction. We conclude with a summary of our growing appreciation of the additional cellular pathways that interconnect with the core mTORC1–ULK1 signalling module.

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