Targeting energy pathways in kidney disease: the roles of sirtuins, AMPK, and PGC1α

Abstract

The kidney has extraordinary metabolic demands to sustain the active transport of solutes that is critical to renal filtration and clearance. Mitochondrial health is vital to meet those demands and maintain renal fitness. Decades of studies have linked poor mitochondrial health to kidney disease. Key regulators of mitochondrial health-adenosine monophosphate kinase, sirtuins, and peroxisome proliferator-activated receptor γ coactivator-1α-have all been shown to play significant roles in renal resilience against disease. This review will summarize the latest research into the activities of those regulators and evaluate the roles and therapeutic potential of targeting those regulators in acute kidney injury, glomerular kidney disease, and renal fibrosis.

Keywords: acute kidney injury; diabetic nephropathy; fibrosis; mitochondria; proteinuria.

Figure 1:

Regulators and Effectors of PGC1α. PGC1α is activated by many transcription factors, including SIRT1, AMPK, TFEB, PKM2, Tug1, and HNF1α. Transcription factors typically involved in inflammatory and pro-fibrotic pathways repress PGC1α, including TLR4, TNFα, TGFβ, PDE4, IL-6. PGC1α activates fatty acid oxidation through PPARs and RXRs. It enhances de novo biosynthesis of NAD+ through mechanisms that have yet to be delineated, and it controls mitochondrial health through activation of ERRα, TFAM, NRF1/2, and SIRT3. Abbreviations: PGC1α - Peroxisome proliferator activated receptor gamma coactivator 1 alpha, SIRT - sirtuin, AMPK - 5’ AMP-activated protein kinase, TFEB - transcription factor EB, PKM2 - pyruvate kinase M2, Tug1 - Taurine Up-Regulated 1, HNF1α - hepatocyte nuclear factor 1 alpha, TLR4 - toll-like receptor 4, TNFα - tumor necrosis factor alpha, TGFβ - transforming growth factor beta, PDE4 - phosphodiesterase 4, IL-6 - interleukin 6, PPARs - Peroxisome proliferator-activated receptors, RXRs - retinoid X receptors, ERRα - estrogen-related receptor alpha, TFAM - transcription factor A, mitochondrial, NRF - nuclear respiratory factor.

Figure 2:

Direct effects of AMPK, Sirtuins, and PGC1α on mitochondrial function. AMPK activates SIRT1 and PGC1α. It also alleviates inhibition of CPT1, which stimulates fatty acid import into the mitochondria, and it activates the primary receptor for DRP1, which initiates mitochondrial fission and impacts mitochondrial dynamics. PGC1α stimulates mitochondrial biogenesis and mitochondrial DNA proliferation through NRF1/2 and TFAM. It increases expression of all complexes of the ETC and increases fatty acid flux through β-oxidation. In the liver and skeletal muscle, PGC1α stimulates expression of UCP. It also activates SIRT3. SIRT3 deacetylases and activates ETC complexes, including ATP Synthase. It activates many mitochondrial enzymes responsible for ROS scavenging, and it deacetylates LCAD, which initiates β oxidation to enhance energy substrate availability in the mitochondria. Abbreviations: AMPK - 5’ AMP-activated protein kinase, PGC1α - Peroxisome proliferator activated receptor gamma coactivator 1 alpha, SIRT - sirtuin, CPT1 - carnitine palmitoyltransferase I, DRP1 - dynamin-1-like protein, NRF - nuclear respiratory factor, TFAM - transcription factor A, mitochondrial, ETC - electron transport chain, UCP - uncoupling protein, ATP - adenosine triphosphate, ROS - reactive oxygen species, LCAD - long-chain acyl-CoA dehydrogenase.

Figure 3:

The Role of PGC1α in AKI. With AKI-induced suppression of PGC1α, mitochondrial biogenesis decreases, and mitochondrial dynamics are altered. The result is an insufficient quantity and lower quality pool of mitochondria. When mitochondrial injury is too significant to be safely disposed through normal mitochondrial dynamics, injured mitochondria undergo fragmentation and release damaging contents into the cells, which leads to increased ROS production and inflammation. The decreased availability of healthy mitochondria combined with reduced expression of ETC complexes, leads to decreased ATP production and cellular energy deprivation. Finally, PGC1α suppression leads to reduced fatty acid flux through β-oxidation with a resultant fatty acid build up that can also be damaging to cellular health. Abbreviations: PGC1α - Peroxisome proliferator activated receptor gamma coactivator 1 alpha, ROS - reactive oxygen species, ETC - electron transport chain, ATP - adenosine triphosphate, NAD - nicotinamide adenine dinucleotide.

Figure 4:

The effects of hyperglycemia on glomerular health. Hyperglycemia inhibits PGC1α by suppressing PGC1α activators PKM2, AMPK, SIRT1, and Tug1 while upregulating PGC1α inhibitors, TLR4 and NFκβ. With decreased PGC1α expression, the glomerulus experiences decreased expression of key podocyte genes, which leads to albuminuria. There is also lipid accumulation and reduction in antioxidant enzymes stimulated by PGC1α with resultant accumulation of oxidative stress, which leads to podocyte apoptosis and mesangial expansion. Abbreviations: PGC1α - Peroxisome proliferator activated receptor gamma coactivator 1 alpha, PKM2 - pyruvate kinase M2, AMPK - 5’ AMP-activated protein kinase, SIRT - sirtuin, Tug1 - Taurine Up-Regulated 1, TLR4 - toll-like receptor 4, NFκβ - nuclear factor kappa-light-chain-enhancer of activated B cells.

Figure 5:

PGC1α regulation of NAD Biosynthesis. NAD+ is metabolized through three pathways. The salvage pathway recycles NAD+ after it is converted to NAM. The Priess-Handler Pathway creates NAD+ from nicotinic acid, and the de novo biosynthesis pathway metabolizes NAD+ from tryptophan. PGC1α expression upregulates the enzymes that comprise the de novo biosynthesis pathway. SIRT1 cleaves NAD to NAM to order to perform its actions, which include stimulation of PGC1α, creating a positive feedback loop. AKI reduces expression of PGC1α, SIRT1, and enzymes of the de novo NAD+ biosynthesis pathway with a resultant reduction in total NAD+. Abbreviations: : PGC1α - Peroxisome proliferator activated receptor gamma coactivator 1 alpha, NAD - nicotinamide adenine dinucleotide, NAM - niacinamide, SIRT - sirtuin, AKI - acute kidney injury, NMN - nicotinamide mononucleotide.