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.

TGF-β1 reprograms metabolism in renal fibroblasts, inducing a switch from oxidative phosphorylation to aerobic glycolysis. However, molecular events underpinning this are unknown. Here we identify that TGF-β1 downregulates acetyl-CoA biosynthesis via regulation of the pyruvate dehydrogenase complex (PDC). Flow cytometry showed that TGF-β1 reduced the PDC subunit PDH-E1α in fibroblasts derived from injured, but not normal kidneys. An increase in expression of PDH kinase 1 (PDK1), and reduction in the phosphatase PDP1, were commensurate with net phosphorylation and inactivation of PDC. Over-expression of mutant PDH-E1α, resistant to phosphorylation, ameliorated effects of TGF-β1, while inhibition of PDC activity with CPI-613 was sufficient to induce αSMA and pro-collagen I expression, markers of myofibroblast differentiation and fibroblast activation. The effect of TGF-β1 on PDC activity, acetyl-CoA, αSMA and pro-collagen I was also ameliorated by sodium dichloroacetate, a small molecule inhibitor of PDK. A reduction in acetyl-CoA, and therefore acetylation substrate, also resulted in a generalised loss of protein acetylation with TGF-β1. In conclusion, TGF-β1 in part regulates fibroblast activation via effects on PDC activity.

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