Integrative Biology of Diabetic Kidney Disease

Abstract

Background: The leading cause of end-stage renal disease in the US is diabetic kidney disease (DKD). Despite significant efforts to improve outcomes in DKD, the impact on disease progression has been disappointing. This has prompted clinicians and researchers to search for alternative approaches to identify persons at risk, and to search for more effective therapies to halt progression of DKD. The identification of novel therapies is critically dependent on a more comprehensive understanding of the pathophysiology of DKD, specifically at the molecular level. A more expansive and exploratory view of DKD is needed to complement more traditional research approaches that have focused on single molecules. Summary: In recent years, sophisticated research methodologies have emerged within systems biology that should allow for a more comprehensive disease definition of DKD. Systems biology provides an interdisciplinary approach to describe complex interactions within biological systems, including how these interactions influence systems' functions and behaviors. Computational modeling of large, system-wide, quantitative data sets is used to generate molecular interaction pathways, such as metabolic and cell signaling networks. Key Messages: Importantly, the interpretation of data generated by systems biology tools requires integration with enhanced clinical research data and validation using model systems. Such an integrative biological approach has already generated novel insights into pathways and molecules involved in DKD. In this review, we highlight recent examples of how combining systems biology with traditional clinical and model research efforts results in an integrative biology approach that significantly adds to the understanding of the complex pathophysiology of DKD.

An integrative systems biology approach for precision medicine in diabetic kidney disease

“…DKD is a complex multifactorial disease with many deregulated processes that initiate and sustain the progression of the disease including but not limited to cell respiration, oxidative stress, metabolic disorders, vascular and endothelial factors, inflammation and fibrosis, angiogenesis and regeneration potential . Research efforts that have targeted single pathways and molecules have had limited impact on our ability to effectively alter the course of the disease course in the past 25 years . Novel alternative approaches are needed to gain a comprehensive understanding of the early disease pathophysiology at the molecular level to improve the clinical impact of basic and translational research.…”

“…Several reviews have outlined the specifics of the underlying techniques used in systems biology with a focus on novel therapeutics development . Here, we will describe recent advances in the discovery and validation of non‐invasive biomarkers for predicting disease progression and response to treatment in DKD.…”

“…5 Research efforts that have targeted single pathways and molecules have had limited impact on our ability to effectively alter the course of the disease course in the past 25 years. 6,7 Novel alternative approaches are needed to gain a comprehensive understanding of the early disease pathophysiology at the molecular level to improve the clinical impact of basic and translational research.…”

“…[13][14][15][16][17] Several reviews have outlined the specifics of the underlying techniques used in systems biology with a focus on novel therapeutics development. 6,7,18,19 Here, we will describe recent advances in the discovery and validation of non-invasive biomarkers for predicting disease progression and response to treatment in DKD. Specifically, we will focus on how systems biology, through more comprehensive understanding of the complexity of DKD, will improve clinical outcome by facilitating the discovery of novel plasma or urinary molecular biomarkers to identify patients at high risk of progression (prognostic markers); and to predict the patients' responses to treatment (predictive markers).…”

Urinary glycated uromodulin in diabetic kidney disease

“…Detection of microalbuminuria is not as sensitive as more invasive techniques, such as renal biopsy. There is an urgent need to identify non-invasive biomarkers of DKD in its early stages [2][3][4][5][6].…”