Targeting Energy Pathways in Kidney Disease: The Roles Of Sirtuins, AMPK, And PGC1α Part 2
Apr 18, 2023
PGC1α and Renal Fibrosis
According to relevant studies,cistanche is a traditional Chinese herb that has been used for centuries to treat various diseases. It has been scientifically proven to possess anti-inflammatory, anti-aging, and antioxidant properties. Studies have shown that cistanche is beneficial for patients suffering from kidney disease. The active ingredients of cistanche are known to reduce inflammation, improve kidney function and restore impaired kidney cells. Thus, integrating cistanche within a kidney disease treatment plan can offer great benefits to patients in managing their condition. Cistanche helps to reduce proteinuria, lowers BUN and creatinine levels, and decreases the risk of further kidney damage. In addition, cistanche also helps reduce cholesterol and triglyceride levels which can be dangerous to patients suffering from kidney disease.
Cistanche's antioxidant and anti-aging properties help to protect the kidneys from oxidation and damage caused by free radicals. This improves kidney health and reduces the risks of developing complications. Cistanche also helps to boost the immune system, which is essential in fighting off kidney infections and promoting kidney health. By combining traditional Chinese herbal medicine and modern Western medicine, those suffering from kidney disease can have a more comprehensive approach to treating the condition and improving their quality of life. Cistanche should be used as part of a treatment plan but is not to be used as an alternative to conventional medical treatments.
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PGC1α and its activators have also been implicated in the progression of fibrotic kidney disease. Transcriptomic analysis of human and mouse kidney tissue with and without fibrosis revealed that fibrotic tissue had lower expression of PGC1α and β-oxidation enzymes and higher lipid content than controls.15 Further investigation showed that the profibrotic cytokine, TGFβ1, suppressed PGC1α.15 Another study examining renal biopsy samples from diabetic patients with and without DKD showed that TLR4 and NFκβ were both highly expressed in diseased kidneys and were associated with PGC1α suppression. Inhibiting TLR4 or NFκβ restored PGC1α and improved the fibrotic phenotype in db/db diabetic mice.121 Yet another study identified increased phosphodiesterase 4 (PDE4) expression in fibrotic renal tissue from a mouse ureteral obstruction model as a driver of PGC1α suppression via cAMP signaling and showed that inhibition of PDE4 with siRNA or selective PDE4 inhibitor, rolipram, attenuated fibrosis.122 Finally, sustained signaling of developmental pathways such as Notch, has been shown to promote fibrosis by suppressing PGC1α and other genes involved in fatty acid oxidation. Overexpression of Notch signaling led to severe fibrosis in mouse models whereas overexpression of PGC1α mitigated Notch-induced fibrosis.123
Independent of external suppression, PGC1α deficiency in knockout mice led to spontaneous tubulointerstitial inflammation with increased expression of inflammatory cytokines and receptors such as IL-6 and TNFα, which are independently linked to fibrosis development.99 Likewise, genetic overexpression of PGC1α, pharmacologic activation of AMPK, and pharmacologic agonism of PGC1α targets, PPARα or PPARγ, protected against fibrosis progression.15, 91, 124, 125 There is little known about the mechanisms utilized by PGC1α to attenuate fibrosis progression. In cultured cells, PGC1α overexpression repressed TGFβ1/Smad signaling, a major pathway associated with fibrosis progression.126 Notably, TGFβ1 itself has been reported to suppress PGC1α, likely creating a reinforcing feedback loop for normal health that switches in response to profibrotic stimuli.127 Although debated, the epithelial-mesenchymal transition (EMT) may play a role in the pathogenesis of renal fibrosis. EMT has been associated with broad-ranging mitochondrial dysfunction including increased cellular oxidative stress, loss of mitochondrial membrane potential, decreased mitochondrial DNA, and decreased expression of ETC complexes—all functions that are regulated by PGC1α.128 Inhibiting mitochondrial replication induced EMT while PGC1α overexpression prevented EMT in cells treated with aldosterone.128
There is optimism that PGC1α related pathways may be clinically useful targets to prevent renal fibrosis. However, fibrotic diseases are less likely to be resolved with acute therapies, and there is currently a severe paucity of data studying the long-term sequelae of PGC1α-associated alterations in mitochondrial metabolism. That will need to be addressed before chronic therapies targeting fibrosis are developed for clinical use.
PGC1α and NAD+ Metabolism
PGC1α regulates NAD+ biosynthesis. As a redox cofactor, NAD+ is involved in most major energy metabolism pathways including glycolysis, the citric acid cycle, β-oxidation of fatty acids, and the ETC. NAD+ also plays a critical role as a substrate for enzymes that execute post-translational modifications to proteins. NAD+ can be biosynthesized through three pathways. Most NAD+ is created through the salvage pathway, which recycles NAD+ via niacinamide (NAM), but NAD+ is also synthesized from niacin through the Preiss-Handler pathway or from tryptophan through the de novo biosynthesis pathway. The metabolomic analysis examined which metabolites were differentially abundant in ischemic kidneys and PGC1α knockout kidneys. Both ischemic kidneys and PGC1α knockout kidneys were deficient in NAM and NAD+. Conversely, mice with tubular-specific PGC1α overexpression had increased NAM. Furthermore, supplementing NAM in PGC1α knockout mice was sufficient to restore normal NAD+ levels, prevent ischemic AKI, and normalize AKI-associated renal fat accumulation.10 RNA sequencing comparing PGC1α overexpressing kidneys to injured post-ischemic kidneys and PGC1α knockout kidneys revealed that PGC1α expression was associated with increased transcript levels of nearly all enzymes in the de novo NAD+ biosynthetic pathway while those enzymes were suppressed in injured kidneys and PGC1α knockout kidneys.10 Urine metabolomic sampling of human AKI samples subsequently showed evidence of de novo NAD+ biosynthetic impairment with specific suppression of quinolinate phosphoribosyltransferase (QPRT), a bottleneck enzyme of the pathway.82 Mouse QPRT knockouts were NAD+ deficient and suffered worse renal injury after IRI. Supplementing NAD+ levels with NAM through the salvage pathway, and thus bypassing the suppressed pathway, mitigated AKI in both QPRT deficient mice and a small pilot randomized placebo-controlled trial of humans undergoing cardiac surgery.82
In addition to biosynthetic impairment, NAD+ is likely consumed at higher rates during AKI, contributing to NAD+ depletion. Poly ADP-ribose polymerases (PARPs) respond to stress as a DNA repair mechanism and cleave NAD+. PARPs were upregulated in a rabbit septic AKI model and were associated with decreased ATP and NAD+. Inhibiting PARPs improved NAD+ and ATP levels and mitigated AKI.129 Likewise, sirtuins consume NAD+, a relationship that may explain many of the similar findings between NAD+ augmentation and sirtuin activation promoting longevity in experimental systems. Sirtuins activate PGC1α, which in turn stimulates NAD+ biosynthesis, thus creating a delicate balance of consumption and production that tightly regulates NAD+ levels (Figure 5).
While it is clear that NAD+ levels are important for cellular health and resilience against renal injury and that PGC1α plays a critical role in that regulation, there is still much to be learned about NAD+ metabolism and regulation. The evolutionary redundancy in the NAD+ biosynthetic pathways hints toward a critical need for this cofactor to be robustly produced, but also to exhibit precisely tunable production. It is interesting that the de novo NAD+ biosynthetic pathway only accounts for roughly 10% of total NAD+ production,130 yet in AKI, that pathway is specifically downregulated to a degree that becomes clinically relevant. Likewise, mutations in this otherwise minor pathway have been linked to renal developmental anomalies,131–133 while mutations in nicotinamide mononucleotide adenylyltransferase 1 (NMNAT1) of the salvage pathway are not associated with renal anomalies despite that pathway’s more significant contribution to NAD+ stores and other clinical findings in those patients consistent with NAD+ deficiency.134 Untangling the individual impacts of the different NAD+ synthesis pathways, despite their redundancy, and elucidating the etiology of the de novo pathway’s critical influence on the kidney, will be essential to understanding the full reach of PGC1α.
Pharmacologic Targeting of the AMPK/ Sirtuin/PGC1α Pathway
As discussed above, many pharmacologic agents impact upstream or downstream effectors of PGC1α. AICAR and resveratrol are two of the more widely studied agents that stimulate PGC1α activators. AICAR, an AMPK agonist increases PGC1α expression and has been shown to reduce the severity of cisplatin-mediated AKI,44 IRI,103 fibrotic myofibroblast activation,124 and hyperglycemia-associated autophagy dysfunction.92 Resveratrol is a notable natural product that activates sirtuins. In models of kidney disease, resveratrol increased AMPK and PGC1α expression and mitigated diabetic nephropathy. 107, 111, 112 Similarly, resveratrol decreased profibrotic signalling47 and renal scarring in a mouse folic acid model.64 In an AKI model, resveratrol reduced the severity of the toxic injury or IRI101, 102, 135 and restored mitochondrial respiratory capacity after hemorrhagic shock.136
NAD+ supplementation has also been demonstrated as a method to achieve PGC1α-like renoprotection by augmenting downstream effects. NAD+ levels decrease in renal injury due to impaired biosynthesis and increased NAD+ consumption. Treatment with NAM not only restored NAD+ levels in mice after ischemic injury but also alleviated the renal fat accumulation and renal insufficiency associated with ischemic and cisplatin injury.10 In a small placebo-controlled randomized clinical trial, oral NAM enhanced NAD+ biosynthesis and reduced AKI after cardiac surgery.82 Another NAD+ precursor, nicotinamide mononucleotide (NMN), protected mouse kidneys from age-associated AKI susceptibility by restoring SIRT1 activity,60 while NAM protected mice from ureteral obstruction-related fibrosis and reduced the expression of fibrotic proteins in TGFβ-stimulated cells.137
Many other agents have been shown to impact PGC1α activity through less clear mechanisms. Salidroside, the active component of the Rhodiola rosea plant, and glycyrrhizic acid, from licorice root both led to increased SIRT1 and PGC1α and protected mice from diabetic nephropathy.138, 139 Another study showed that melatonin could also stimulate AMPK activity and PGC1α expression to protect mice from diabetic kidney injury.140 Agonists of the 5HT1F serotonin receptor were shown to increase mitochondrial proteins, increase PGC1α, and accelerate renal recovery after IRI.141 Green tea extracts also increased PGC1α and protected mice against cyclosporine-induced renal injury.142
However, despite the many available and promising options for modulating these energy pathways to protect against acute and chronic renal disease, no treatment has advanced to clinical practice. Many of the above approaches lack the necessary specificity for modulating PGC1α. Moreover, only limited data are available about the long-term effects of activating PGC1α. The kidney offers a prime example of this challenge. Renal tubular cells respond well to PGC1α overexpression with acute protection from injury, while podocytes within the same organ experience a detrimental hyperproliferation in response to PGC1α overexpression. Yet, those same podocytes that do not respond well to PGC1α overexpression do seem to respond well to upstream PCG1α activators or agonism of PPARγ. The challenges with targeting PGC1α in the kidney also extend to considerations of other organs. For example, cardiac PGC1α overexpression reduces pathological remodeling of aging hearts in some studies,143 while it led to dilated cardiomyopathy144 and reduced tolerance to cardiac ischemia145 in others. The long-term cardiac effects of a systemically administered PGC1α activator targeting renal disease may thus impede clinical development. These examples emphasize the importance of continuing to identify mechanisms underlying the AMPK-Sirtuin-PGC1α axis.
Conclusions
Through bountiful studies, a clear link has been established between mitochondrial health and renal resilience against AKI, glomerular disease, and fibrosis. Key regulators of mitochondrial pool health, namely AMPK, sirtuins, and PGC1α, are emerging as promising therapeutic targets. The hurdle that must now be overcome is translating these insights safely from the bench to the bedside. To do that, the intricate web connecting all of these regulators must continue to be unwound. Perhaps rather than targeting master regulators such as AMPK and PGC1α, safer therapies may emerge from an increased understanding of downstream effectors. There is also a great need to understand the organ and cell-specific roles of these effectors as individual tissues respond differently to metabolic-based therapies based on their innate requirements for fuel and energy production. Overall, the goal of prescribing metabolic rehabilitation as a form of renal therapy revolving around PGC1α and its regulators holds enormous promise.
Energy Pathways and Emerging Renal Drugs: SGLT2 Inhibitors and HIF Stabilizers
While not yet definitely linked to the AMPK-Sirtuin-PGC1α axis, two emerging drug classes are likely to impact renal metabolism in beneficial ways. Sodium-glucose cotransporter 2 (SGLT2) inhibitors are now widely used to treat type 2 diabetes by inhibiting renal glucose reabsorption. SGLT2 inhibitors have been shown to reduce AKI, progression to end-stage renal disease, and death.146 In addition to improved glycemic control, kidney protection may be afforded by metabolic alterations in renal tubular cells. A recent study showed that diabetes led to hyperactivation of mTOR complex 1, which caused ATP production to shift from lipolysis to ketosis in proximal tubules. SGLT2 inhibitors increased ketone body levels, which ameliorated diabetes-associated reduction in renal ATP and nephropathy in mice.147 Another study used imaging mass spectrometry to show that Krebs cycle metabolites abnormally accumulated in the renal cortex of diabetic mice, reflecting increased utilization of this pathway to metabolize excess glucose. SGLT2 inhibition converted the metabolite profile back to wild-type ratios in which the largest fractions of metabolites were from glycolysis.148 Finally, data from renal tubule cells showed that both insulin and glucose reabsorption suppressed gluconeogenesis by reducing SIRT1-mediated PGC1α activation and SGLT2 inhibition abrogated this effect.149
Less widely used currently but emerging as a powerful drug class to treat CKD-related anemia, hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitors, called HIF stabilizers, also exert metabolic effects in the kidney. In renal tubule cell culture and kidneys of streptozotocin-treated rats, HIF stabilizers reduced Krebs cycle flux and increased basal glycolysis.150 Functionally, HIF stabilizers have been shown to reduce albuminuria in diabetic rodent models and to reduce the accumulation of lipid peroxidation products.150, 151
Targeting energy pathways of renal tubule cells may prove beneficial for treating an array of kidney diseases. Future studies for SGLT2 inhibitors and HIF stabilizers may identify novel connections to the AMPK-SIRT-PGCα axis. Regardless, the emergence of these two drug classes suggests promise for applying insights from energy metabolism to renal pharmacology.
Financial Support:
AJC is supported by NIH grant K12-HD000850. SMP’s laboratory is supported by grants from the National Institutes of Health: R35-HL139424; R01-DK095072; R01-AG027002; and R01-HL125275
For more info: david.deng@wecistanche.com WhatApp:86 13632399501
