Implications of microRNA in kidney metabolic disorders
ExRNA volume 2, Article number: 4 (2020)
The kidney requires large amount of energy to regulate the balance of fluid, electrolytes and acid-base homeostasis. Mitochondria provide indispensible energy to drive these functions. Diverse energy sources such as fatty acid and glucose are fueled for ATP production at different renal sites controlled by a fine-tuned regulation mechanism. microRNAs (miRNAs) have been implicated in the pathogenesis of various kidney diseases. Recent studies have highlighted their contributions to metabolic abnormalities. Characterization of the miRNAs in renal metabolic disorders may promote a better understanding of the molecular mechanism of these diseases and potentially serve as therapeutic targets.
The kidney requires a large amount of energy to enable the reabsorption of nutrients and regulation of electrolytes, fluid and acid-base balance. Maintenance of metabolic homeostasis is critical to functioning of the kidney and possibly requires a fine-tuned regulation mechanism. Global analysis has demonstrated that various metabolic disorders are corrected with the alternation of microRNA (miRNA) expression profile, suggesting vital roles of miRNAs in maintaining organ energy homeostasis.
miRNAs are small non-coding RNAs of ~ 22 nucleotides that regulate gene expression at the post-transcriptional level. miRNA is transcribed from intergenic, intronic or polycistronic loci as precursor RNAs (pri-miRNA) in canonical biogenesis pathway . The stem-loop structure from the pri-miRNA is processed by Drosha and DGCR8 or the nuclear spliceosome apparatus. As an alternative way, miRNAs are non-canonically transcribed as endogenous short hairpin RNAs (shRNAs) or derive through splicing from introns (mirtrons) . Then the pre-miRNA are transported to the cytosol by exportin-5 and Ran-GTP-dependent processes and are further processed by complex of RNase III, Dicer and TRBP to form the mature miRNA. miRNA duplex is then unwind by argonaut proteins (Ago2) and incorporates into the argonaut-containing RNA-induced silencing complex (RISC). The RISC-miRNA assembly is then guided to specific target sequences in mRNAs chiefly located in the 3’UTR by Watson-Crick base-pairing of nucleotides 2–8 in the mature miRNA, also called the seed sequence .
In this review, we briefly introduce the metabolic feature of the kidney and then discuss the advances in understanding the emerging roles of miRNAs in modulating metabolic disorders, particularly on mitochondrial homeostasis, lipid and glucose metabolism.
Metabolic characterizations of the kidney
The kidney functions to remove waste and regulate fluid and electrolyte balance. The active reabsorption of glucose, sodium and other metabolites from glomerular filtrate is a power task [4,5,6] that makes the kidney one of the most energy-demanding organ and the highest resting metabolic rates in our body . To provide sufficient energy, the kidney is equipped with the highest mitochondrial content and consumes most of the oxygen only secondary to the heart [8, 9]. Moreover, the proximal convoluted tubular cells and the thick ascending loop of Henle (TAL) cells in the kidney cortex contain the majority of the renal mitochondria [10,11,12,13,14] which use the majority of kidney consumed oxygen to generate ATP [4,5,6].
In healthy conditions, large quantities of the renal ATP are produced within the mitochondria via oxidative phosphorylation (OXPHOS) [5, 14, 15]. Electrons from NADH and FADH2 produced by tricarboxylic acid (TCA) cycle are transferred to complex I and complex II, respectively and then through complex III to complex IV to be accepted by oxygen. Concurrently, protons are pumped across the membrane through complexes I, III and IV, and ultimately, flow through complex V (ATP synthase) to drive the production of ATP from ADP.
Different renal sites have diverse fuel preference (Table 1). The tubulointerstitial compartment except the glomeruli, utilize free fatty acid (FFA) via β-oxidation and ketone oxidation for ATP generation . Glucose oxidation is preferred in the TAL and the glomerular cells. Whereas, glucose anaerobic metabolism occurs in the more hypoxic renal medulla . Aerobic metabolism of a single molecule of glucose produces 36 molecules of ATP which is more efficient than the production of 2 molecules of ATP by anaerobic metabolism . The FFA oxidation, such as a molecule of palmitic acid produces 106 molecules of ATP, is even more efficient . It is worth note that proximal tubular cells (PTCs) produce glucose from lactate, glutamate and glycerol via gluconeogenesis [18, 19] that also require ATP [20, 21]. The ATP is also required for glomerular filtration and for the synthesis of hormone and proteins, although ATP for these processes are much lower than the reabsorption . The fuel preferences tend to reflect the energy demands at different renal sites in the physiological conditions. The ATP production and energy source is actually flexible. Glomerular cells, including podocytes, endothelial cells and mesengial cells have the ability of aerobic and anaerobic respiration in basal cell processes [22,23,24,25]. In the absence of glucose, amino acid can be alternatively utilized to generate pyruvate to fuel glycolysis and OXPHOS [26, 27] (Fig. 1).
Taken together, many renal cells have high metabolic rates and are highly dependent on mitochondrial generation of ATP to maintain their physiological morphology and functions.
miRNA regulates lipid metabolism
Fatty acid is one of the major energy sources of the kidney similarly to the heart [16, 28]. The key components of fatty acid oxidation are targets of various miRNAs. Carnitine palmitoyltransferase 1α (CPT1α) mediates the entrance of fatty acid to mitochondria , which has been shown to be targeted by miR-33 family [30, 31] and miR-370 . miR-142 targets CPT1α to regulate metabolic reprogramming during immunogenic response .
Carnitine ctanoyl transferase (CROT) is a peroxisomal enzyme that allows short chain fatty acid to enter into the mitochondria . miR-33a, miR-33b and the complementary strand miR-33a-3p has been found to target CROT and therefore affect fatty acid β oxidation [30, 31, 34]. Moreover, the intronic region of sterol-regulatory element binding proteins (SREBP2)  and SREBP1  genes encode miR-33a and miR-33b, which also targets the 3-ketoacyl-coA thiolase to regulate fatty acid oxidation . In addition, miR-33a and miR-33b was found to target sirtuin SIRT6 , a NAD+-dependent histone deacetylase [38,39,40,41]. miR-33 inhibits SIRT6 and leads to acetylation of SREBP1 targeted acetyl-coA carboxylase 1 (ACC1), stearoyl-coA desaturase 1 and fatty acid synthase (FASN), which results in repression of lipogenesis .
miR-122 antisense significantly reduces plasma cholesterol level [42, 43]. Transfecting of miR-122 reduces the transcription of aldolase-A in hepatocarcinoma cell line . Pantothenate kinase 1 (PANK) is involved in the synthesis of coenzyme A, which is a cofactor in lipid metabolism . In the intronic sequence of the PANK1α gene locates the miR-103 and miR-107 which affects lipid metabolism . miR-224 targets acyl-coA synthetase long chain family (ACSL4)  and alters fatty acid oxidation .
Gene expression profiling identifies the upregulation of a group of lipid metabolic genes in the absence of miR-21, including the direct target of miR-21, peroxisome proliferator activated receptor α (PPARα) . miR-21 promotes renal fibrosis by targeting PPARα and Mpv171 to silence lipid metabolic pathway and aggravates ROS generation, respectively . Moreover, miR-21 silencing enhances PPARα/retinoid X receptor and the downstream pathways that protects mitochondrial function and relieves inflammation and fibrogenesis in renal tubule and glomeruli . miR-17 is identified as a novel target for treatment of autosomal dominant polycystic kidney disease (ADPKD), which is the downstream of c-myc and inhibit OXPHOS and stimulate proliferation to aggravate cyst growth via directly repress of PPARα . Similarly, miR-105 regulates the sustained cell growth by targeting MYC .
PPARδ mediates the metabolic switch from fatty acid oxidation to glycolysis . miR-199a targets PPARδ to increase lipid accumulation and affects mitochondrial content in heart and liver . PPARδ is also the target of miR-29a .
AMP-dependent kinase (AMPK) signaling and insulin receptor signaling pathways are critical cellular energy pathways such as lipid and glucose metabolism . AMPKα1 is targeted by miR-33a and miR-33b [37, 55], which mediates the inhibition of SREBP or phosphorylation and deactivation of SREBP-targeted ACC1 [56, 57]. The insulin receptor substrate 2 (IRS2), one of the adaptor proteins that relays insulin receptor signaling to the downstream effectors, is also the target of miR-33 . Reduced IRS2 and compensatory elevation of IRS1 activates SREBP1 , which explains the effect of miR-33 on lipid deposition and hepatosteatosis.
In summary, these results suggest an integrated and extensive interaction between the targets and their miRNAs to regulate lipid metabolism (Fig. 2).
miRNA modulates glucose metabolism and glycolysis related signaling pathways
Several miRNAs regulates the tissue responses to insulin and glucose metabolism. In diabetes, miR-29a and miR-29b are upregulated in muscle and liver , which repress insulin signaling stimulation protein caveolin 2 (CAV2) [60, 61], SREBP negative regulator insulin-induced gene 1 (INSIG1) and insulin intermediate PI3 kinase subunit p85α . miR-126 targets IRS1 to induce insulin signaling inhibition . miR-223 inhibit glucose uptake in skeletal muscle by targeting glucose transporter GLUT4 . miR-103 and miR-107 are probably therapeutic targets for relieving insulin resistance . They affect the availability of insulin receptor by targeting CAV1 . Interestingly, miR-103 and miR-107 are inhibitors of Dicer and their effects are also presumably mediated via other miRNAs . miR-143 is high in diabetic db/db mice and contributes to the reduced insulin signaling sensitivity possibly by targeting Akt related oxysterol-binding protein-related 8 (ORP8) . let-7 miRNA family, also increased in diabetic mice probably results in impaired insulin signaling through targeting insulin-like growth factor 1 receptor (IGF1R) and IRS2 .
In proliferative cells such as tumor, several miRNAs have been found to directly target enzymes and transporters involved in the process of glycolysis. Downregulation of miR-106a results in de-repression of GLUT3 and promotes glycolysis [21, 69, 70]. Similarly, downregulation of miR-195-5p leads to de-repression of its target GLUT3 and increases the uptake of glucose in bladder cancer . miR-144 targets GLUT1 which results in reduced glucose uptake and lactate production in lung cancer cells . GLUT1 is also the target of miR-1291 and miR-328 in renal cell carcinoma  and colon cancer cell , respectively.
The glycolytic enzyme hexokinase 2 (HK2) is the direct target of miR-143 . In addition, HK2 is indirectly regulated by miR-124 and miR-155 both via STAT3 [76, 77]. miR-128, miR-135 and miR-320 target phosphofructokinase (PFK) which is downregulated in lung cancer [78,79,80]. SIRT2 specifically targeted by miR-200c is a critical regulator of several glycolytic enzymes, including aldolase, glyceraldehyde-3-phosphate dehydrogenase (GAPDH), phosphoglycerate kinase (PGK), and enolase .
Pyruvate kinase type M2 (PKM2) is targeted by let-7a . Moreover, c-Myc targeted by let-7, is also the activator of hetergenous nucler ribonucleoprotein A1 (hnRNPA1) splicing factor, which in turn downregulates let-7 and forms a positive feedback loop consisting of let-7a/c-Myc/hnRNPA1/PKM2 . PKM2 is also the target of miR-326 in regulation of cell proliferation . PKM2 is targeted by miR133a/b in tongue squamouse cell carcinoma [84,85,86]. The PKM2 targeted by miR-122 is shown to induce metabolic switch from glycolysis to OXPHOS . miR-340, miR-124 and miR-137 target the alternative splicing proteins hnRNPI/hnRNPA1/hnRNPA2, which make the PK PKM2 . miR-26a targets pyruvate dehydrogenase protein X (PDHX) to promote glycolysis and repress OXPHOS .
miR-34 targets lactate dehydrogenase A (LDHA) and is also reduced in breast cancer [90, 91]. LDHB is the target of miR-375 [92,93,94]. miR-124 and miR-342-3p target lactate monocarboxylate transporter 1 (MCT1) to inhibit the transport of lactate from cytosol to extracellular space [95, 96].
Besides insulin receptor signaling, glycolytic metabolism is also regulated by receptor tyrosine kinases (RTKs) and the downstream effecter pathways, including c-Met, platelet-derived growth factor receptor α (PDGFRA), epidermal growth factor receptor (EGFR), RAS pathway, PI3K/Akt, mTOR and c-myc. c-Met is targeted by miR-410 , miR-144-3p , and miR-34a [99,100,101,102]. In addition, miR-34a also targets PDGFRA . miR-128 targets PDGFRA and EGFR . Furthermore, EGFR is the target of miR-219-5p [104, 105] and miR-7 [106, 107].
miR-9-targeted NF1 is the antagonist of RAS . N-RAS is the target of miR-143  and miR-340 [110, 111]. K-RAS is targeted by let-7a  and miR-134 . Most of the miRNAs are aforementioned as glycolytic targeting miRNAs, suggesting a strong correlation between RAS and glycolysis.
Activation of PI3K/Akt pathway contributes to the enhanced glycolysis. miR-7 directly targets PI3K . The downstream Akt is targeted by miR-542-3p . miR-21 indirectly regulates PI3K through targeting its antagonist PTEN . Moreover, PTEN is the target of miR-26a , miR-1908 , miR-494-3p , miR-10a/b , and miR-21/221 [121, 122].
The PI3K/Akt downstream pathway mTORC1 is the promoter for glycolysis and negatively regulated by AMPK. mTORC1 is indirectly regulated by miR-451 via targeting CAB39, which binds the AMPK activator LKB1 [123, 124]. miR-199a-3p targets mTORC1 and mTORC2 . miR-34a suppresses Rictor, which is the binding partner of mTORC2 [101, 126].
In conclusion, multiple miRNAs have been shown to affect glucose homeostasis (Fig. 3) and insulin signaling pathway (Fig. 4). The regulatory loops composed of miRNA/glycolysis related signaling pathways/glycolysis are possibly universal in proliferative cells.
miRNA in amino acid metabolism
Synthesis and breakdown of amino acid are mainly occurs within the mitochondria. The amino acid is also the energy source of renal tubular cells . Previous studies have shown that amino acid metabolism is regulated by multiple miRNAs. miR-193b regulates serine hydroxyl transferase (SHMT2), which converts serine to glycine . miR-23a and miR-23b have been implicated in proliferative cells to control the expression of glutaminase in mitochondria . Interestingly, their downregulation following c-myc overexpression is also observed during sustained cell proliferation and transformation . The target of miR-29b, digydrolipoyl branched chain acyltransferase is one of the components of branched chain α-ketoacid degydrogenase, which mediates the catabolism of leucin, isoleucine and valine .
miRNA modulates the mitochondrial homeostasis
mitomiRs and mitochondria
miRNAs that locate inside the mitochondria are termed mitomiRs, either encoded by the mitochondrial genome or transported into the organelle [132, 133]. miRNAs are not expressed in cells without mitochondrial DNA (mtDNA) suggests that human and mouse mitochondrial genome could encode miRNAs . Moreover, the presence of pre-miR and the corresponding mature miRNAs in mitochondria suggests that miRNA processing may occur in the mitochondria. It is possible that nuclear-encoded miRNAs may be imported into mitochondria [133, 135, 136] where to regulate mtDNA translation . MitomiRs have distinguishable characteristics that separate them from cytosolic miRNA, such as an unusual size between 17 and 25 nt and unique thermodynamic features, which are speculated to facilitate their entry to mitochondria . Multiple putative mitomiR binding sites were revealed on the mtDNA in silico studies ; however, evidence showing the import of miRNA into mitochondria is still lacking. Isolation of mitochondria without the contamination of other membrane vesicles remains the major technical obstacle and interpretation of the data should be taken with caution. Whether mitochondria-produced miRNA can be exported to the cytoplasm is still controversial. The mitochondrial-like transcripts probably come from mitochondrial genome equivalents within the nuclear genome [137,138,139].
Evidence of mitomiRs in renal cells remains poorly noticed. The muscle-specific miR-1 enhances mtDNA-encoded transcripts inside the mitochondria of cardiac and skeletal muscle ; however, the direct evidence showing the binding of miR-1 to mitochondrial transcripts was lacking. It is also interesting because the translational stimulation effect of miRNAs was merely reported previously. The rat cardiac-specific mitomiR, miR-181c is enriched 2-fold in mitochondria compared to the whole heart, which targets the mRNA of cytochrome c oxidase subunit I (COX1) and regulates mitochondrial respiration . In addition, administration of miR-181c regulates mitochondrial genes and leads to cardiac dysfunction . More reports indicate the role of miR-181a in regulation of mitochondrial apoptosis pathway . In cisplatin-induced acute kidney injury (AKI), repression of mitochondrial resident protein Bcl-1 by miR-181 leads to proximal tubular cells injury . Recent research reveals a panel of aging-related mitomiRs (let7b, miR-146a, −133b, −106a, −19b, −20a, −34a, −181a and − 221) targets a number of mitochondrial resident proteins besides Bcl-1 . miR-378 binds to the mitochondrial transcriptome locus of ATP6, which is a subunit of the F0 complex of the complex V (ATP synthase) and finally impacts ATP generation . During the process of skeletal muscle maturation, miR-1/133a targets the Mef2A/Dik1-Dio3 gene cluster and modulates the expression of multiple miRNAs which then suppress the mitochondrial genes .
Conformation of the existence of mitomiRs in the kidney tissue and exploration of their pathophysiologic functions will be of great interest and promising.
Canonical miRNA and mitochondria
It is shown that a couple of canonical miRNAs regulates mitochondrial functions including TCA, OXPHOS via mechanisms in the cytosol. Brain-specific miRNA, miR-338 reduces nuclear genome encoded cytochrome c oxidase subunit IV (COX4), which regulates ROS level . Under hypoxic conditions, miR-210 is markedly induced and directly represses OXPHOS by targeting the iron-sulfur cluster scaffold (ISCU) and cytochrome c oxidase assembly protein (COX10), which ultimately contributes to the metabolic shift from OXPHOS to glycolysis [148, 149]. Moreover, miR-210 could regulate complex II activity by targeting its subunit succinate dehydrogenase subunit D (SDHD) . miR-335 and miR-34a target mitochondrial superoxide dismutase 2 (SOD2) and thioredoxin reductase 2 (TR2) and therefore regulate oxidative damage and cell senescence . Increased NADPH oxidase resulted from the decrease of miR-25 in diabetic kidney causes oxidative stress in mesenchymal cells .
The enzyme activity of pyruvate dehydrogenase (PDH) is reduced when its subunit X is targeted by miR-26a, which leads to accumulation of pyruvate with decrease of acetyl-coA . It has been reported that citrate synthase (CS) is targeted by several miRNAs, including miR-152, −148a, −148b, − 299, −19a, −19b, −122a, − 421 and − 494 .
miR-124 downregulates succinate coA ligase GDP forming β subunit (SUCLG2) and represses the conversion of succinate to succinyl coA . Downregulation of isocitrate dehydrogenase (IDH) by miR-183 and malate dehtdrogenase (MDH) by miR-743a within the TCA cycle results in a metabolic shift toward glycolytic status . The ADP-ribosylation factor-like 2 (ARL2) is a common target for miR-15b, − 16, − 195, − 424 , which affects mitochondrial degradation and ATP production .
Other miRNAs have been implicated in modulation of mitochondrial dynamics. miR-30 family member are found to regulate Drp1 by targeting p53 . Notably, miR-30/p53/Drp1 limits mitochondrial fission and promotes mitochondrial fusion, which has been suggested to be particularly important in high energy demanding organs such as the cardiac tissue . miR-30/p53/Drp1 axis may also prevent the loss of cells with less self-renewal capacity by the increase of threshold for apoptotic activation . This might be identified in kidney tissues that have the similar physiologic features.
miR-26 promotes mitochondrial uncoupling and induces energy dissipation in brown adipocytes by increasing uncoupling protein 1 (UCP1) and leads to a slight increase of cristae density . Additionally, miR-27a and miR-27b were shown to regulate mitochondrial biogenesis, structure integrity and complex I activity during adipogenesis by targeting prohibitin . The miR-149/poly (ADP-ribose) polymerase-1 (PARP-1)/NAD+/SIRT-1 axis increases mitochondrial function and biogenesis through PGC-1α activation in skeletal muscle .
miR-378 downregulates caspase 3 and inhibits apoptosis in cardiac tissue . The aforementioned miR-1 targets insulin-like growth factor (IGF), decreases mitochondrial membrane potential and leads to the release of caspase 3 .
In summary, increasing evidences suggest that these mitochondrial functional regulating miRNAs are possibly mitomiRs and mediate nuclear regulation of mitochondrial functions and mitochondrial retrograde cellular adaptive signals (Fig. 5).
Conclusion and perspective
Thousands of miRNAs have been shown to regulate numerous aspects in human physiological and pathological conditions. As we mentioned here, a growing number of miRNAs have been implicated in regulating metabolic disorders and maintaining mitochondrial homeostasis (Table 2). This could suggest similar regulatory roles of miRNAs in kidney metabolic diseases. It is necessary to carry out functional validation studies in human and models of kidney diseases to establish such link between miRNA expressions and their regulatory role in renal metabolic disorders. Moreover, as compared to traditional medications toward several druggable targets, the potential therapeutic implications for treatment of kidney diseases by targeting the aberrant miRNAs seem exciting in the clinical perspective. However, proteins are probably regulated by plenty of miRNAs because of the multiple target sites in mRNAs. In addition, miRNAs always have many target proteins because of the similar target sequences in mRNAs. The possible off-target effect and long-term consequences of miRNA-targeted therapeutics remain unknown. These will certainly be the topics for intensive research in the near future.
Availability of data and materials
Acyl-coA synthetase long chain
Autosomal dominant polycystic kidney disease
Acute kidney injury
ADP-ribosylation factor-like 2
Cytochrome c oxidase
Carnitine palmitoyltransferase 1α
Carnitine ctanoyl transferase
Epidermal growth factor receptor
Fatty acid synthase
Free fatty acid
Hetergenous nucler ribonucleoprotein A
Insulin-like growth factor
Insulin-like growth factor 1 receptor
Insulin-induced gene 1
Insulin receptor substrate
Iron-sulfur cluster scaffold
Monocarboxylate transporter 1
Oxysterol-binding protein-related 8
Poly (ADP-ribose) polymerase-1
Platelet-derived growth factor receptor α
Pyruvate dehydrogenase protein X
Pyruvate kinase type M2
Peroxisome proliferator activated receptor
Proximal tubular cells
RNA-induced silencing complex
Receptor tyrosine kinases
Serine hydroxyl transferase
Short hairpin RNAs
Superoxide dismutase 2
Sterol-regulatory element binding proteins
Succinate coA ligase GDP forming β subunit
Thick ascending loop of Henle
Thioredoxin reductase 2
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This work was supported by Key Program of National Natural Science Foundation of China 81530022, General Program of National Natural Science Foundation of China 81873618 and National Natural Science Foundation for Young Scholars of China 81600526.
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Zhou, Y., Yang, J. Implications of microRNA in kidney metabolic disorders. ExRNA 2, 4 (2020). https://doi.org/10.1186/s41544-019-0042-9
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