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Mitochondrial energetics in the kidney.... "Hyperglycaemia is the main factor that contributes to the development of diabetic nephropathy"
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"Hyperglycaemia is the main factor that contributes to the development of diabetic nephropathy.....Mitochondrial energetics are altered in diabetic nephropathy owing to increased ROS and hyperglycaemia.....Hyperglycaemia increases the production of NADH and FADH2 by the TCA cycle, fueling the ETC183. ROS released from the ETC can damage mtDNA....Mitochondrial energetics are altered in diabetic nephropathy owing to increased ROS and hyperglycemia....Mitochondrial fragmentation has been observed in proximal tubules in the early stages of diabetes mellitus....Hyperglycaemia also stimulates the conversion of glucose to fructose via the polyol pathway in proximal tubules, leading to ATP depletion"
Nature Reviews Nephrology 14 August 2017
ABSTRACT: The kidney requires a large number of mitochondria to remove waste from the blood and regulate fluid and electrolyte balance. Mitochondria provide the energy to drive these important functions and can adapt to different metabolic conditions through a number of signalling pathways (for example, mechanistic target of rapamycin (mTOR) and AMP-activated protein kinase (AMPK) pathways) that activate the transcriptional co-activator peroxisome proliferator-activated receptor-γ co-activator 1α (PGC1α), and by balancing mitochondrial dynamics and energetics to maintain mitochondrial homeostasis. Mitochondrial dysfunction leads to a decrease in ATP production, alterations in cellular functions and structure, and the loss of renal function. Persistent mitochondrial dysfunction has a role in the early stages and progression of renal diseases, such as acute kidney injury (AKI) and diabetic nephropathy, as it disrupts mitochondrial homeostasis and thus normal kidney function. Improving mitochondrial homeostasis and function has the potential to restore renal function, and administering compounds that stimulate mitochondrial biogenesis can restore mitochondrial and renal function in mouse models of AKI and diabetes mellitus. Furthermore, inhibiting the fission protein dynamin 1-like protein (DRP1) might ameliorate ischaemic renal injury by blocking mitochondrial fission.
CONCLUSIONS: Mitochondrial homeostasis involves a network of cellular processes that regulate ATP production; the disruption of these processes can result in mitochondrial dysfunction and organ damage. Although much is known about mitophagy and mitochondrial fission, fusion and biogenesis, the precise role of these processes in renal disease remains to be determined. It is clear, however, that mitochondrial dysfunction is common and occurs early in AKI and diabetic nephropathy. Furthermore, the absence of recovery of mitochondrial function after diverse insults might lead to the continued impairment of renal function, leading to CKD. As renal cell repair and the recovery of renal function is dependent on the ability of mitochondria to produce ATP, restoring mitochondrial function might reverse cellular injury and restore renal function, particularly for diseases such as AKI and diabetic nephropathy. Collectively, the available studies corroborate the need to target mitochondrial homeostasis to restore mitochondrial function and stimulate organ repair or prevent further declines in organ function.
Targeting PPARs
PPARs can regulate cellular metabolism, mitochondrial function, mitochondrial biogenesis, fatty acid oxidation and glucose homeostasis; thus, targeting them could be beneficial for patients with renal disease related to mitochondrial dysfunction.
Collectively, the available studies corroborate the need to target mitochondrial homeostasis to restore mitochondrial function and stimulate organ repair or prevent further declines in organ function.
Activation of PPARs can ameliorate ischaemic AKI207, 208, 209. As discussed above, an accumulation of fatty acids and increased ROS production can decrease the efficiency of the ETC. Defects in fatty acid oxidation have been attributed to the downregulation of PPARs during renal ischaemia18. Fenofibrate, which is used to treat dyslipidaemia, activates PPARα210 (Table 1). Activation of PPARα leads to activation of lipoprotein lipase, which hydrolyses triglycerides into glycerol and free fatty acids for metabolism210. PPARs can also stimulate mitochondrial biogenesis; for example, compounds such as bardoxolone increase the level of PPARG (encoding PPARγ) and NFE2L2 (encoding NRF2) mRNA, leading to mitochondrial biogenesis211. However, the use of bardoxolone in clinical trials for patients with type 2 diabetes mellitus and stage 4 CKD showed adverse effects in patients, including an increase in the rate of heart failure events, resulting in termination of the trial212.
The efficacy of PPAR agonists in animal models suggests these agents could show promise for the treatment of diabetic nephropathy. Treatment of db/db diabetic mice with fenofibrate led to decreased hyperglycaemia and insulin resistance, potentially by correcting glucose homeostasis213. Studies have also shown that treatment of diabetic mice with fenofibrate leads to a decrease in fatty acids in the kidney, supporting its potential as a therapeutic for diabetic nephropathy214, 215, 216. These in vivo studies provide evidence that fenofibrate might be suitable for the treatment of patients with diabetic nephropathy. Indeed, fenofibrate decreased dyslipidaemia and albuminuria in patients with type 2 diabetes mellitus and reduced the risk of further cardiovascular events217. Taken together, these studies confirm that PPARs have a role in diabetic nephropathy and are a therapeutic target.
The administration of formoterol in a model of IRI accelerated the recovery of mitochondrial and renal function by 6 days174. LY344864 is a potent 5-HT1F agonist; it induced mitochondrial biogenesis in naive mice and accelerated the recovery of mitochondrial biogenesis and renal function in the same AKI model175. Several GPCR ligands, such as atrasentan, are currently in clinical trials of diabetic nephropathy; however, whether they act by influencing mitochondrial energetics is unknown and requires further research. These studies provide a foundation for pursuing the targeting of GPCRs, particularly β2AR and 5-HT1F, as a treatment for mitochondrial dysfunction in renal diseases.
Diabetic nephropathy
Diabetic nephropathy is the leading cause of end-stage renal disease (ESRD) in the USA177, 178. It is characterized by hyperglycaemia, albuminuria, the accumulation of extracellular matrix proteins, and glomerular and tubular epithelial hypertrophy, as well as a reduced glomerular filtration rate following an initial period of hyperfiltration179. Mitochondrial energetics are altered in diabetic nephropathy owing to increased ROS and hyperglycaemia180, both of which induce changes in the ETC that cause a decrease in ATP production and an increase in apoptosis180. In line with these observations, increased fission, mitochondrial fragmentation and reduced levels of PGC1α are all observed in the early stages of diabetes mellitus181, 182. Structural changes in mitochondria correlate with the observed changes in mitochondrial energetics182.
Hyperglycaemia is the main factor that contributes to the development of diabetic nephropathy (Fig. 7). Hyperglycaemia increases the production of NADH and FADH2 by the TCA cycle, fueling the ETC183. ROS released from the ETC can damage mtDNA, hindering the production of mitochondrial proteins183. The hyperglycaemic state was originally thought to cause mitochondrial dysfunction by stimulating the development of hyperpolarized mitochondria, which produce more ATP and release higher levels of superoxide from complexes I and III than healthy mitochondria180, 184, 185. Administration of antioxidants such as vitamin E and vitamin A did not, however, attenuate the complications of patients with diabetes mellitus, suggesting that mitochondrial ROS might not be the primary mediator of mitochondrial dysfunction in diabetic nephropathy186. Hyperglycaemia can also increase the level of advanced glycation end products (AGEs), and the activity of the protein kinase C (PKC) and hexosamine pathways, which can contribute to mitochondrial dysfunction187. All three events cause deleterious effects that include increased fibrosis, thrombosis, oxidative damage and abnormalities in the vasculature and in blood flow187.
Hyperglycaemia also stimulates the conversion of glucose to fructose via the polyol pathway in proximal tubules, leading to ATP depletion188. A role for endogenous fructose metabolism in the regulation of diabetic nephropathy was suggested by a study showing that deleting the gene that encodes ketohexokinase (KHK; also known as hepatic fructokinase) - the enzyme responsible for the conversion of fructose to fructose-1-phosphate - protected mice from streptozotocin-induced diabetic nephropathy189. Proximal tubules are a major site of ketohexokinase expression188, 190 and ATP levels were increased and tubular morphology was improved in diabetic Khk−/− mice compared with that of diabetic wild-type mice, suggesting a role for fructose metabolism in the pathogenesis of diabetic nephropathy189.
Mitochondrial fragmentation has been observed in proximal tubules in the early stages of diabetes mellitus181, although the mechanisms that drive changes in mitochondrial dynamics in diabetes are not yet clear. Fission dissipates the mitochondrial membrane potential, decreasing the production of ATP and promoting apoptosis191. Several studies have suggested a role for RHO-associated protein kinase 1 (ROCK1) signalling in activating fission in the diabetic kidney192. ROCK1 promotes the translocation of DRP1 to the mitochondria and triggers fission by phosphorylating DRP1 (Ref. 192). Deletion of ROCK1 in mice with streptozotocin-induced diabetes prevents mitochondrial fission, attenuates the increase in ROS production and restores bioenergetic function in the kidney192.
Patients with diabetes mellitus have reduced levels of the fusion protein MFN2193. In line with this finding, kidney-specific overexpression of MFN2 protects rats from streptozotocin-induced diabetic nephropathy193. MFN2 overexpression decreased ROS production, decreased kidney volume and attenuated the pathological changes seen in the diabetic kidney193. Induced in high glucose 1 (IHG1; also known as THG1L) is another protein that is involved in mitochondrial fusion and has been shown to regulate mitochondrial dynamics and biogenesis in the diabetic kidney194. IHG1 can enhance the ability of MFN2 to bind to GTP and interacts directly with MFN2 to mediate fusion194. Inhibition of IHG1 reduces ATP production and hinders fusion in vitro194. IHG1 also stabilizes PGC1α activation195.
Reduced levels of PGC1α have also been observed in diabetic rat kidneys196. The overexpression of PGC1α in mesangial cells in vitro attenuated the pathophysiological changes induced by hyperglycaemic conditions196. The decrease in mitochondrial biogenesis in diabetic rat kidneys is consistent with the translocation of DRP1 to the mitochondrial outer membrane and an increase in mitochondrial fragmentation196. The levels of PGC1α mRNA and protein were also reduced in podocytes that were cultured under hyperglycaemic conditions compared with the levels in podocytes that were cultured under normal glucose conditions, indicating a decrease in mitochondrial biogenesis197.
Another study has described an important role for pyruvate kinase M2 (PKM2) in diabetic nephropathy. The expression and activity of PKM2 is upregulated in patients with long-term diabetes mellitus who have not developed diabetic nephropathy but not in patients with diabetic nephropathy198. Podocytes from PKM2-knockdown mice have decreased PPARGC1A mRNA and mitochondrial mass, whereas activation of PKM2 attenuated the decrease in mitochondrial function and glycolytic flux in podocytes in vitro. In vivo studies showed that activation of PKM2 in mice attenuated the diabetes-induced decrease in PPARGC1A mRNA and increased the expression of OPA1, increasing mitochondrial fusion198. Activation of PKM2 can therefore reverse mitochondrial dysfunction and renal abnormalities associated with diabetes mellitus. These studies highlight the need for further research in this area, as targeting the balance between mitochondrial biogenesis and dynamics could be a potential therapeutic approach for diabetic nephropathy.
The kidney is one of the most energy-demanding organs in the human body. A study measuring the resting energy expenditure of various organs in healthy adults, ranging from 21 to 73 years of age, found that the kidney and heart have the highest resting metabolic rates1.
The kidney has the second highest mitochondrial content and oxygen consumption after the heart2, 3. The resting metabolic rate for the kidney is high because the kidney requires an abundance of mitochondria to provide sufficient energy to enable it to remove waste from the blood, reabsorb nutrients, regulate the balance of electrolytes and fluid, maintain acid-base homeostasis, and regulate blood pressure. These tasks, especially the reabsorption of glucose, ions and nutrients through channels and transporters, are driven by ion gradients.
Mitochondria provide energy to the Na+-K+-ATPase to generate ion gradients across the cellular membrane4. In the kidney, the proximal tubule, the loop of Henle, the distal tubule and the collecting duct all require active transport to reabsorb ions4. By contrast, glomerular filtration is a passive process that is dependent on the maintainence of hydrostatic pressure in the glomeruli5. Proximal tubules require more active transport mechanisms than other renal cell types because they reabsorb 80% of the filtrate that passes through the glomerulus, including glucose, ions, and nutrients. As such, they contain more mitochondria than any other structure in the kidney. The ability of mitochondria to sense and respond to changes in nutrient availability and energy demand by maintaining mitochondrial homeostasis is critical to the proper functioning of the proximal tubule. In this Review, we describe the processes involved in maintaining mitochondrial homeostasis and discuss how these processes provide and maintain sufficient energy to support renal function. We also explore how disease states, such as acute kidney injury (AKI) and diabetic nephropathy, alter mitochondrial function, and how mitochondrial energetics might be targeted as a treatment for these diseases.

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