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

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.

Metabolic Regulation of Fibroblast Activation and Proliferation during Organ Fibrosis

“…Enhanced glycolytic flux alone cannot meet the high metabolic demands of fibroblasts, and increased carbon supply through alternate pathways is needed to support urgent biosynthetic requirements [71]. Conversion of glutamine to α-ketoglutarate (α-KG) is termed glutaminolysis (shown in Fig.…”

“…Fibroblasts from human fibrotic kidneys are inherently more proliferative and synthesize more collagen than their counterparts from normal and healthy kidneys. Apart from the anaplerotic flux of biosynthetic metabolites, glutamine can also be used in the synthesis of amino acids for collagen synthesis to satisfy the increased demands of ECM synthesis, including glycine and proline, which are the two most abundant amino acids in collagen protein, as mentioned above, altogether constituting over 50% of the primary structure of collagen [71]. Glycine is synthesized de novo from serine (which is produced from glucose and glutamate via serine hydroxymethyltransferase).…”

Metabolic Reprogramming in Kidney Diseases: Evidence and Therapeutic Opportunities

“…Consequently, the metabolic switch to aerobic glycolysis reduces the expression of acetyl-CoA, which upregulates histone 3-related gene expression [ 22 ] and increases the expression of fibrotic genes [ 23 ]. In addition, the enhanced glutamine metabolism is needed to support the biosynthetic requirements of renal myofibroblasts [ 24 ]. This metabolic reprogramming is highly correlated with the development of renal interstitial fibrosis [ 25 ].…”

Novel Therapeutic Targets in Liver Fibrosis

“…Proinflammatory and pro-fibrotic cytokines can activate HSCs to release their stored vitamin A, proliferate, and produce ECM, with the cells adopting a high metabolic state (Chen et al, 2012;Higashi et al, 2017). In this way, HSCs undergo dramatic metabolic changes to meet the increased bioenergetic and biosynthetic demands of mitogenesis and ECM synthesis (Xie et al, 2015;Para et al, 2019;Zhao et al, 2020;Hewitson and Smith, 2021). These metabolic changes are often accompanied by increased glycolysis and mitochondrial respiration in order to optimize glucose consumption in HSCs and redirect them to support fibrogenic transdifferentiation (Lian et al, 2016).…”