A Metabolic Reprogramming of Glycolysis and Glutamine Metabolism Is a Requisite for Renal Fibrogenesis-Why and How?

Timothy D Hewitson,Timothy D Hewitson,Edward R Smith

doi:10.3389/fphys.2021.645857

Timothy D Hewitson, Timothy D Hewitson + Show 1 more

Open Access

https://doi.org/10.3389/fphys.2021.645857

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Abstract

Chronic Kidney Disease (CKD) is characterized by organ remodeling and fibrosis due to failed wound repair after on-going or severe injury. Key to this process is the continued activation and presence of matrix-producing renal fibroblasts. In cancer, metabolic alterations help cells to acquire and maintain a malignant phenotype. More recent evidence suggests that something similar occurs in the fibroblast during activation. To support these functions, pro-fibrotic signals released in response to injury induce metabolic reprograming to meet the high bioenergetic and biosynthetic demands of the (myo)fibroblastic phenotype. Fibrogenic signals such as TGF-β1 trigger a rewiring of cellular metabolism with a shift toward glycolysis, uncoupling from mitochondrial oxidative phosphorylation, and enhanced glutamine metabolism. These adaptations may also have more widespread implications with redirection of acetyl-CoA directly linking changes in cellular metabolism and regulatory protein acetylation. Evidence also suggests that injury primes cells to these metabolic responses. In this review we discuss the key metabolic events that have led to a reappraisal of the regulation of fibroblast differentiation and function in CKD.

Highlights

While the kidney can recover from acute injury, persistent and/or severe injury results in the chronic accumulation of scar tissue and progressive renal failure
While a major focus of fibrosis research has been on the transcriptional regulation of collagen synthesis, we appreciate that transforming growth factor-β1 (TGF-β1) is a trigger for a metabolic reprogramming that is needed for fibroblast synthesis and contraction
Analysis of the canonical pathways differentially regulated by TGF-β1 identified inhibition of acetyl-CoA biosynthesis via inactivation of pyruvate dehydrogenase complex (PDC) as a potential metabolic regulator of fibroblast activation in cells derived from fibrotic kidneys (Smith and Hewitson, 2020)

Summary

Introduction

While the kidney can recover from acute injury, persistent and/or severe injury results in the chronic accumulation of scar tissue (fibrosis) and progressive renal failure. While a major focus of fibrosis research has been on the transcriptional regulation of collagen synthesis, we appreciate that TGF-β1 is a trigger for a metabolic reprogramming that is needed for fibroblast synthesis and contraction.

Results

Conclusion