PGC1α in the kidney

Abstract

Acute kidney injury (AKI) arising from diverse etiologies is characterized by mitochondrial dysfunction. The peroxisome proliferator-activated receptor γ coactivator-1alpha (PGC1α), a master regulator of mitochondrial biogenesis, has been shown to be protective in AKI. Interestingly, reduction of PGC1α has also been implicated in the development of diabetic kidney disease and renal fibrosis. The beneficial renal effects of PGC1α make it a prime target for therapeutics aimed at ameliorating AKI, forms of chronic kidney disease (CKD), and their intersection. This review summarizes the current literature on the relationship between renal health and PGC1α and proposes areas of future interest.

INTRODUCTION

Among organs with the highest energy demands, the kidney is second only to the heart in mitochondrial abundance (54). The kidney requires a constant ATP supply to transport solutes against electrochemical gradients along the nephron. Mitochondria are densely localized to the renal tubular epithelium and are particularly abundant in the proximal tubule and medullary thick ascending limb of Henle (70), to aid in the critical functions of solute reabsorption and secretion. Mitochondria are the dynamic organelles responsible for energy production (ATP) in the cell via oxidative phosphorylation. The electron transport chain (ETC) pumps protons from the inner mitochondrial matrix to the intermembrane space, creating an electrochemical gradient across the inner mitochondrial membrane that powers the phosphorylation of ADP to ATP. The highly charged state of the inner membrane is prone to leakage of electrons along the ETC, becoming a source of reactive oxygen species (ROS) that can cause oxidative stress on the cell. Excess mitochondrial ROS production during ischemia or inflammation may accelerate injury in acute kidney injury (58, 77, 78).

Mitochondrial Injury and the Quality Control Cycle

Mitochondria form dynamic tubular networks, constantly undergoing fission and fusion to adapt to the ever-changing energy demands of the cell. Dynamin-related protein-1 (Drp1) mediates fission and translocates from the cytosol to the outer mitochondrial membrane, where it facilitates division of the mitochondrion into short rods or spheres. In fusion, the mitofusin proteins (Mfn1 and Mfn2) from the outer membrane interact with the inner membrane protein, optic atrophy 1 (Opa1), to produce elongated fusiform mitochondria (96). Fission may initiate autophagic degradation of defective mitochondria via mitophagy, promote apoptosis, and generate additional ROS (23). Fusion can enhance oxidative phosphorylation and mitigate the number of damaged mitochondria by combining their contents with healthy mitochondria through complementation (94). An intricate balance of these mitochondrial dynamics is necessary to maintain the mitochondrial network and overall organelle morphology and function. Dysregulation of mitochondrial dynamics has been implicated in neurodegenerative, cardiovascular, and genetic diseases (4).

Structural alterations in renal mitochondria have been observed in human and animal models of AKI. Electron microscopy of renal proximal tubule cells have revealed severe mitochondrial vacuolization and swelling with diffusely arranged cristae in septic (79, 80), ischemic (8, 55, 81), and toxin-mediated AKI (52, 99). Along with structural changes, diminished electron transport chain enzyme activity in the septic kidney confirms overall mitochondrial dysfunction (80).

Beyond overt changes in morphology, mitochondrial dynamics are also interrupted in the injured mitochondrion during AKI. Brooks et al. (8) observed mitochondrial fragmentation and Drp1 mobilization to the outer mitochondrial membrane in injured tubular cells. Drp1 activation recruited apoptogenic proteins such as Bax and Bak, leading to cytochrome c release and initiation of apoptosis. Utilizing dominant-negative mutants, RNA interference, and chemical inhibitors, the authors further demonstrated that Drp1 inhibition attenuated mitochondrial fragmentation, preserved mitochondrial integrity and function, and limited apoptosis following cisplatin or ischemic injury. In turn, kidney function was better preserved. Jiang et al. (36) showed that rapamycin treatment in mice enhanced mitophagy and ameliorated cisplatin nephrotoxicity. Conversely, pharmacological inhibition or genetic deletion of autophagy-related genes worsened renal injury. These and other studies suggest that excessive fission during AKI is deleterious to organ function, whereas safe clearance of damaged mitochondria via mitophagy may be protective (7, 32).

PGC1α Mechanisms in Mitochondrial Biogenesis and Quality Control

In conjunction with timely clearance of damaged mitochondria, generation of healthy mitochondrial mass may be important in recovery from AKI. PGC1α has emerged as a key regulator of mitochondrial biogenesis. PGC1α also has critical roles in essential metabolic processes such as fatty acid oxidation, oxidative phosphorylation, and ROS detoxification (61, 87, 92). The PGC-1 family of proteins includes PGC1α, PGC1β, and PGC-1 related coactivator. These proteins share functional overlap in non-kidney cells due to similarities in protein structure (44, 45). PGC1α has been the most extensively studied in renal cells and mammalian kidneys, with several isoforms identified from promoter and alternative splicing studies conducted in studies of skeletal muscle (14, 44, 45, 50, 66).

PGC1α was discovered by Spiegelman’s group (61) as a cold-inducible regulator of adaptive thermogenesis in brown adipose tissue. This group quickly thereafter demonstrated PGC1α’s role in mitochondrial biogenesis by activation of the transcription factor NRF-1 leading to transcription of Tfam and genes encoding respiratory chain proteins (92). As a transcriptional cofactor, PGC1α expression can be induced by various external and physiological stimuli such as exercise (33), nutrient deprivation (65), hypoxia (2), cAMP activation (91), and oxidant stress (74). PGC1α is also subject to posttranslational modifications that alter its activity. For example, phosphorylation by AMPK or deacetylation by Sirt1 increases PGC1α action (10, 33). AMPK, Sirt1, and PGC1α monitor and respond to the energy requirements of the cell in a highly coordinated fashion (9). PGC1α acts as a cofactor for yin-yang 1 (YY1) to promote mitochondrial biogenesis. This interaction with YY1 is positively modulated by the mammalian target of rapamycin (mTOR), suggesting this particular pathway is induced only when there are available nutrients to create energy stores (19). Genes encoding proteins for mitochondrial processes such as fatty acid oxidation are regulated by estrogen-related receptors (ERRs) and PPARα, both of which can be activated by PGC1α (31, 84).

Beyond mitochondrial biogenesis, there is also evidence PGC1α plays a role in mitochondrial dynamics and mitophagy. Soriano et al. (72) demonstrated PGC1α-mediated coactivation of estrogen-related receptor α-induced Mfn2 in skeletal muscle and brown adipose tissue. Vainshtein et al. (82) demonstrated loss of PGC1α decreased exercise-induced autophagic flux and mitophagy in skeletal muscle of C57BL/6 mice via decreased transcription of autophagy-related genes. This group also found PGC1α knockout mice had decreased lipid transport to the lysosome compared with their wild-type littermates secondary to downregulation of exercise-induced increases in Niemann-Pick C1.

PGC1α in Cardiometabolic Processes

Abundant PGC1α is found in metabolically active organs including the brain, skeletal muscle, heart, and the kidney (61). In skeletal muscle, PGC1α has been shown to promote angiogenesis following ischemia by inducing vascular endothelial growth factor in a manner independent of the transcription factor HIF (hypoxia-inducible factor) (2). In a trauma-hemorrhage rat model, Hsieh et al. (29, 30) demonstrated that upregulation of PGC1α by estrogen promoted cardiac recovery whereas loss of PGC1α prevented it. PGC1α may exert cardioprotective angiogenic effects in the heart during the stress of pregnancy (56). Recently, Craige et al. (17) showed that PGC1α overexpression decreased angiotensin II-mediated hypertension via increased endothelial nitric oxide synthase expression. PGC1α has also been found to play a role in the homeostasis of other organ systems. Several lines of investigation propose a link to neurological disorders. For example, PGC1α overexpression mitigates experimental models of Parkinson’s disease (98), Huntington’s disease (18, 74, 88), and Alzheimer’s dementia (62).

In diabetes, PGC1α plays a complex role. PGC1α is involved in hepatic gluconeogenesis (60, 64). Thus PGC1α can worsen blood glucose (68). Overexpression of PGC1α in fetal pancreatic β-cells has been shown to decrease β-cell proliferation and function, which is not seen in isolated adult-onset PGC1α overexpression (83), leading to glucose intolerance. However, single-nucleotide polymorphisms influencing PGC1α expression may contribute to the development of type II diabetes mellitus (53), with overexpression of PGC1α perhaps protective in this case (46).

Renal Actions of PGC1α

In the kidney, PGC1α expression is localized to the cortex and outer stripe of the medulla, overlapping with regions of high mitochondrial activity (80). Given the relative abundance of mitochondria found in the kidney compared with other organs, it is perhaps of little surprise PGC1α is increasingly studied by the nephrology community. As damaged mitochondria are apparent in multiple forms of AKI, attention has focused on how PGC1α and mitochondrial biogenesis may promote recovery in the injured kidney. Several studies now demonstrate the key role PGC1α plays in mitigation of AKI, and there is increasing evidence that loss of PGC1α contributes to the development of renal fibrosis and subsequent CKD.

PGC1α in sepsis-associated AKI.

In a fluid-resuscitated endotoxemic model of sepsis, renal PGC1α levels corresponded to the severity of kidney dysfunction both at the nadir of kidney function and during functional recovery following volume expansion (80). Transcript levels of fatty acid oxidation and oxidative phosphorylation genes downstream of PGC1α were also proportionally suppressed relative to the severity of renal injury. This intimate relationship between kidney PGC1α expression and renal function was further confirmed in a complementary surgical model of polymicrobial sepsis. Applying the endotoxemic model to global and renal proximal tubule PGC1α knockout mice, loss of PGC1α exacerbated renal injury. Moreover, both the global and kidney-specific PGC1α-deficient mice sustained persistent renal impairment whereas their control counterparts recovered renal function following volume expansion. Together, these results suggested that renal PGC1α restoration may be necessary for functional recovery of the septic kidney.

Mechanistic studies by Smith et al. (71) have demonstrated a pathway by which lipopolysaccharide (LPS) leads to PGC1α suppression. The decrease in PGC1α and mitochondrial biogenesis in mice treated with intraperitoneal LPS was attenuated by both antibodies directed against toll-like receptor 4 (TLR4) and the extracellular signal-regulated kinase (ERK) pathway, thus suggesting that LPS stimulation of TLR4 leads to ERK activation and downstream PGC1α suppression seen in sepsis-related AKI. A preliminary study by Matejovic et al. (49) using a porcine model of sepsis found a possible genomic predisposition to AKI in sepsis. Pigs developing sepsis-related AKI had lower renal transcript levels of PGC1α, as well as lower cyclooxygenase-2 and angiotensin type II receptor, compared with those that did not develop AKI.

PGC1α in toxin-mediated AKI.

Reduced PGC1α levels have also been observed in the context of toxin-mediated AKI. Despite limited tubular necrosis, Portilla et al. (59) observed that PGC1α expression is diminished along the mouse proximal tubule and thick ascending limb within 24 h of cisplatin-induced AKI. In subsequent cellular studies, they found that cisplatin not only inhibits binding activity of transcription factors to the nuclear receptor (and PGC1α transcriptional partner) PPARα, but also downregulates PGC1α and fatty acid oxidation genes. In folate-induced nephrotoxicity, Ruiz-Andres et al. (67) found that the proinflammatory cytokine TWEAK suppressed PGC1α expression by histone deacetylation and activation of NF-κB signaling, providing other molecular targets to preserve PGC1α in the injured kidney. In nonrenal models, expression of PGC1α has been shown to be repressed by activators of NF-kB (12, 22, 27, 75, 76, 86).

As described above, PGC1α, AMPK, and sirtuin enzymes are tightly interconnected to modulate energy homeostasis. Morigi et al. (51) found that the mitochondrial-specific Sirt3 is suppressed in the kidneys of cisplatin-treated mice similar to PGC1α itself. Treatment with the AMP mimetic compound AICAR—which activates AMPK—attenuated renal injury and preserved PGC1α and Sirt3 levels. Conversely, Sirt3-deficient mice suffered worse kidney injury, which could not be ameliorated by AMPK activation. In vitro studies revealed that Sirt3 prevented Drp1-driven mitochondrial fragmentation and preserved mitochondrial integrity.

PGC1α in renal ischemia-reperfusion.

Renal ischemia-reperfusion injury (IRI) disrupts mitochondrial homeostasis as evidenced by acquired defects in mitochondrial oxidative phosphorylation, the balance of mitochondrial fusion vs. fission, and the downregulation of PGC1α and its target transcription factors (24). Activation of pathways upstream of PGC1α has been shown to improve renal cellular health and renal function in models of IRI. For example, AICAR treatment attenuated nitrosative stress, tubular necrosis, and renal impairment in a rat IRI model (40). Analogously, treatment with the Sirt1 activator SRT1720 improved mitochondrial biogenesis and function in oxidant-stressed renal proximal tubule cells (24). Treatment with SIRT1720 was also shown to decrease renal injury scores, apoptosis, and serum creatinine when given intravenously to rats at the end of 60 min of bilateral renal ischemia (38). Further analysis of these samples revealed those treated with SIRT1720 had improved renal mitochondrial mass, ATP concentration, and PGC1α expression 24 h after reperfusion. Stimulation of Sirt1 via caloric restriction has also been shown to decrease IRI-induced AKI (41). Compared with control littermates, rats fed a 70% calorie-restricted diet for 2 wk before IRI have a smaller rise in serum creatinine, lower renal injury histopathology scores, enhanced Sirt1 induction, and attenuation of IRI-related decrease in PGC1α. The β-adrenergic agonist formoterol strongly induced mitochondrial biogenesis and protected against IRI, leading the team to hypothesize a renoprotective action for PGC1α (35). Collier et al. (15) found that inhibition of ERK1/2 with trametinib led to increased renal FOXO1 and PGC1α. In a mouse IRI model, pretreatment with trametinib before 18 min of bilateral IRI lessened the decrease in PGC1α and NRF1.

Studies directly testing PGC1α as a potential target in renal IRI reinforce the results obtained from the above upstream chemical activation studies. Rasbach and Schnellmann (63) demonstrated that PGC1α overexpression improved mitochondrial function and cell survival in culture models of oxidant injury. Recent work from our group applied both gain and loss of function strategies to study PGC1α in an organismic context. Tran et al. (81) found that PGC1a knockout mice suffered worse renal function and tubular injury, whereas tubule-specific PGC1a overexpressing transgenic mice exhibited less severe AKI, better renal perfusion, quicker restoration of renal function, increased survival, and less histological injury. To explore downstream effector mechanisms of PGC1α, RNAseq and metabolomic analyses of injured kidney tissue identified de novo NAD+ biosynthesis as the main mediator of PGC1α-dependent protection.

NAD+ is a critical cofactor involved in important cellular oxidation-reduction reactions in the Krebs cycle and oxidative metabolism. NAD+ levels are maintained by a balance between biosynthesis and consumption via cleavage enzymes. Three biosynthetic pathways include 1) the Preiss-Handler pathway from niacin, 2) de novo from amino acids including tryptophan, and 3) salvage from nicotinamide (Nam). Of these, NAD+ synthesis from Nam is considered the major mammalian source of NAD+ (16). Along with its role in redox reactions, NAD+ is cleaved to Nam and ADP-ribose by major cell-regulatory enzymes of different classes: sirtuins, poly(ADP ribose) polymerases (PARPs), and ectonucleotidases (85).

In our studies (81), NAD+ biosynthetic enzyme levels positively correlated with overall PGC1α expression. Injured mice had reduced levels of NAD+ and its precursor Nam, and decreased renal function compared with sham-operated controls. At baseline, PGC1α knockout exhibited lower renal levels of Nam and NAD+ than wild-type controls; following IRI, KO mice developed more severe renal function impairment. Conversely, tubule-specific PGC1α-overexpressing mice exhibited higher renal Nam and NAD+ levels at baseline and greater resistance to functional impairment after IRI. Remarkably, Nam supplementation in ischemic PGC1α-null mice was sufficient to augment renal NAD+ and normalize renal function. We also found Nam to be renoprotective when administered in wild-type mice after the onset of AKI and in a toxic AKI model. Notably, an independent study has validated this core finding by administering the direct biosynthetic product of Nam, NMN (nicotinamide mononucleotide), in mouse models of renal IRI and toxic AKI (25).

NAD+ itself is rate-limiting for oxidative metabolism (5, 6), so methods to defend its level in AKI should enhance energy metabolism. The fall in renal NAD+ associated with different kinds of AKI may relate both to decreased biosynthesis and increased consumption—e.g., via stress-activated PARPs. Nam may act as a PGC1α-mimetic by stimulating NAD+ biosynthesis chemically rather than transcriptionally. Consistent with a shared effect on NAD+ augmentation and improved energy metabolism between Nam and PGC1α, we found that either strategy reduced the accumulation of storage fats in the postischemic tubule and increased the level of renal β-hydroxybutyrate, a breakdown product of fatty acid oxidation, which in turn increased vasodilation by activating a G protein-coupled receptor that signals the secretion of prostaglandin E₂. Indeed, blockade of either the hydroxybutyrate receptor or prostaglandin synthesis abrogated the renoprotection conferred by excess tubular PGC1α (81).

PGC1α and renal fibrosis.

PGC1α has been shown to be a key mediator in prevention of experimental renal fibrosis, contributing to excitement around its potential to target CKD. Kidney biopsy specimens derived from individuals with known CKD consistently demonstrate decreased PGC1α expression compared with healthy controls (37, 69, 81). To explore potential underlying mechanisms, Kang et al. (37) performed gene expression profiling on microdissected biopsy samples derived from a cohort of patients with CKD secondary to diabetes or hypertension, comparing those patients to controls without CKD. PGC1α-related fatty acid oxidation transcripts were found to be downregulated in those with CKD. This finding was further studied in a murine model of folate nephropathy where tubular epithelial cell PGC1α transcript levels were reduced and lipid accumulation increased in mice with nephropathy compared with control. They showed that the profibrotic cytokine, TGFβ-1, led to SMAD-3-dependent repression of PGC1α transcription in vitro (37). This study was followed up by Han and colleagues subsequently reported that proximal tubule expression of the AMPK regulator called protein liver kinase B1 (LKB1) helped defend PGC1a expression (27a). Recently, this group also found HES1, a downstream target of the potent regulator of kidney fibrosis, Notch1, directly binds to the PGC1α promoter region, negatively regulating its transcription (28). Additionally, overexpression of PGC1α in vitro or in an in vivo model of tubule-specific Notch1 overexpression decreased profibrotic gene expression and development of renal fibrosis, respectively.

PGC1α and diabetic kidney disease.

Comparing the urinary metabolome in individuals with diabetes both with and without kidney disease led Sharma’s group (69) to propose a role for renal PGC1α in diabetic kidney disease. They found decreased PGC1α mRNA expression in microdissected cortical tubulointerstitial samples in kidney biopsies from those with diabetic kidney disease vs. those with minimal change disease, supporting the argument that loss of renal PGC1α may be an important step in the pathogenesis of diabetic kidney disease.

Several studies have yielded evidence that PGC1α’s involvement in diabetic kidney disease may extend out of the tubule and into glomerular cells. Guo et al. (26) found that PGC1α overexpression decreased mesangial hypertrophy in a rat model of diabetic nephropathy, and Danesh’s group (47) has reported that the long noncoding RNA, Tug1—which enables PGC1α to bind its own promoter—is downregulated in the setting of hyperglycemic stress. Rescue with podocyte-restricted Tug1 overexpression prevented the mitochondrial changes associated with diabetic nephropathy and ameliorated the diabetic kidney phenotype. Although PGC1α’s renal expression is highest in the tubule (80), these results suggest that PGC1α may also mitigate forms of CKD through actions directly in the glomerulus.

Li and colleagues (43a) also found decreased PGC1α transcription and protein levels in the podocytes of microdissected biopsy samples from humans with known diabetic kidney disease as well as two different murine models of diabetic kidney disease. However, podocyte-specific inducible overexpression of PGC1α not only failed to improve outcomes in the murine models, but actually accelerated progression toward end-stage renal disease by inducing collapsing focal and segmental glomerulosclerosis, suggesting a critical window of PGC1α activity required for glomerular health.

PGC1α and uremic extrarenal manifestations.

Relatively less work has explored the role of PGC1α in the context of extrarenal manifestations of CKD or ESRD. One such study began with the premise that PGC1α may be a bellwether for general health. In their study of a cohort of peritoneal dialysis patients, Zaza et al. (95) found decreased PGC1α transcription in peripheral blood monocytes compared with healthy controls. Another study has proposed that fatty acid transport across the vascular endothelium may drive insulin resistance—a feature of progressive renal disease (73)—in a fashion modulated by PGC1α (34).

PGC1α as a drug target in AKI and CKD.

The preponderance of evidence points to loss of tubular PGC1α as a deleterious event in the kidney arising from different stimuli such as inflammatory and profibrotic cytokines. Conversely, enhanced PGC1α expression in the renal tubule has so far proven effective in models of AKI or fibrosis. Given the opportunity to mitigate AKI and CKD with a single target, PGC1α is a very attractive candidate for “kidney chemoprevention.” Indeed, the search for druglike molecules that can modulate PGC1α’s function is, itself, an area of active investigation (3, 97). The exact mechanisms of PGC1α’s protective effects in AKI are not yet fully elucidated. Additionally, no untoward short-term renal effects of increasing PGC1α have thus far been reported. Thus the short-term use of an agent to increase PGC1α expression or action may be a promising approach to prevent AKI in the setting of insults such as suprarenal vascular surgery, cardiothoracic surgery requiring cardiopulmonary bypass, or early in the setting of septic shock.

What is less certain is the feasibility of long-term metabolic therapy for the prevention of chronic kidney disease development. First, little is known about long-term effects of systemic PGC1α upregulation in humans. In mice, in addition to possible development of focal and segmental glomerulosclerosis, it appears that unchecked cardiac PGC1α overexpression may actually be detrimental as such animals develop a dilated cardiomyopathy (39) and suffer decreased tolerance to ischemia (48). Second, although PGC1α’s location downstream of the intensively investigated drug targets, AMPK and sirtuins, should make it somewhat more specific, PGC1α itself has a multitude of downstream targets with varied functional consequences. For example, PGC1α in the skeletal muscle promotes angiogenesis after ischemia, an effect thus far not observed in the kidney and perhaps undesirable in a chronic context (2, 81). Additionally, it has been shown that inhibition of mTOR with rapamycin can decrease renal fibrosis in a KIM-1 overexpression model of CKD in zebrafish and mice (93). Although this study highlights the potential role of autophagy and mitophagy in the prevention of renal fibrosis and CKD, it also calls into question the salutary effects of PGC1α on CKD, as rapamycin would similarly inhibit the mitochondrial biogenesis derived from the mTOR-PGC1α-YY1 axis. Given these unknowns, further defining the critical salutary pathways downstream of PGC1α may offer therapeutic possibilities with better safety profiles. Our study linking PGC1α renal action to NAD+ biosynthesis may be one such example (81).

Another example may come from PGC1α’s effect on PPARα. Portilla’s group (42, 43) demonstrated striking renoprotection against AKI and CKD with PPARα overexpression in the tubule. Aquilano et al. (1) have demonstrated that the lipid accumulation and increased oxidative stress found in sarcopenia is secondary to the decline in adipose triglyceride lipase, regulated by PGC1α via PPARα. PPARα was also recently shown to be critical to the prevention of renal fibrosis in a murine model of diabetic kidney disease (11). Further exploration into the antioxidant and lipid metabolism from this pathway in broader studies may prove beneficial.

A third downstream target of PGC1α is nuclear factor erythroid 2-related factor 2 (Nrf2). Wu et al. found that mice given a single dose of the Nrf2 activator bardoxolone methyl 3 h before IRI had a smaller rise in creatinine and lower histopathology scores 24 h after reperfusion (90). Augmentation of Nrf2 with bardoxolone methyl has also been shown to minimize aristolochic acid-induced AKI (89). BEACON, a large clinical trial of bardoxolone methyl, examined whether Nrf2 activation could slow progression to end-stage renal disease or death from cardiovascular events in patients with diabetes and advanced chronic kidney disease (20). Unfortunately, BEACON was terminated early due to significantly more cardiac events, particularly heart failure, occurring in those receiving bardoxolone methyl. Post hoc analysis, however, found confounding factors such as poor patient selection and decreased bioavailability of angiotensin-2 receptor antagonists induced by enhanced Nrf2 expression that may have contributed to the negative overall result (13, 57). Thus further exploration of Nrf2 enhancement and its implications in renal health are merited.

Conclusions

Decades of research applying techniques across biochemistry, molecular biology, physiology, and human genetics have carefully linked the health of mitochondria to the overall health of the kidney (21). As a master regulator of mitochondrial biogenesis, PGC1α offers exciting possibilities for application to renal diseases. PGC1α has been found to be critical in protection from diverse AKI-inducing stressors, and loss of tubular PGC1α leads to enhanced susceptibility to AKI and long-term renal fibrosis. These findings make the PGC1α pathway an attractive target for AKI and CKD prevention and treatment, with several modulators of PGC1α currently identified (Fig. 1). As the effectors downstream of PGC1α are further elucidated, more targeted approaches may be unveiled in our ongoing efforts to decrease the burden of renal disease.

Fig. 1.

PGC1α and key modulators. AMP kinase, Sirtuin enzymes, and PGC1α comprise a circuit that senses and responds to stressors that affect energy metabolism. Depicted are biological and chemical modulators of this circuit that have been implicated in renal studies of PGC1α as described in the text. Arrows indicate positive interactions. “T” arrows indicate inhibitory interactions.

GRANTS

S. M. Parikh’s laboratory is supported by National Institutes of Health (NIH) Grants R01-DK-0950972, R01-HL-125275, and R01-HL-093234. M. R. Lynch is supported by NIH Grant T32-DK-007199.

DISCLOSURES

S. M. Parikh is listed as an inventor on patent applications filed by Beth Israel Deaconess Medical Center regarding PGC1α and NAD+.

AUTHOR CONTRIBUTIONS

M.R.L. and M.T.T. prepared figures; M.R.L. and M.T.T. drafted manuscript; M.R.L., M.T.T., and S.M.P. edited and revised manuscript; M.R.L., M.T.T., and S.M.P. approved final version of manuscript.