d-arg-dmt-lys-phe-nh2 and Acute-Kidney-Injury

AKI is associated with high morbidity and mortality, and it predisposes to the development and progression of CKD. Novel strategies that minimize AKI and halt the progression of CKD are urgently needed. Normal kidney function involves numerous different cell types, such as tubular epithelial cells, endothelial cells, and podocytes, working in concert. This delicate balance involves many energy-intensive processes. Fatty acids are the preferred energy substrates for the kidney, and defects in fatty acid oxidation and mitochondrial dysfunction are universally involved in diverse causes of AKI and CKD. This review provides an overview of ATP production and energy demands in the kidney and summarizes preclinical and clinical evidence of mitochondrial dysfunction in AKI and CKD. New therapeutic strategies targeting mitochondria protection and cellular bioenergetics are presented, with emphasis on those that have been evaluated in animal models of AKI and CKD. Targeting mitochondrial function and cellular bioenergetics upstream of cellular damage may offer advantages compared with targeting downstream inflammatory and fibrosis processes.

Topics: Acute Kidney Injury; Adenosine Triphosphate; Animals; Humans; Mitochondria; Oligopeptides; Renal Insufficiency, Chronic

This study aimed to assess the effect and mechanism of SS31 on cisplatin-induced acute kidney injury (CP-AKI) both in vivo and in vitro.. Male mices and HK-2 cells were treated using cisplatin to establish models of CP-AKI. 32 C57BL/6 mices were randomly divided into four groups (control group, CP group, CP + normal saline group, CP + SS-31 group). Cisplatin was intraperitoneally injected once to the mice (25 mg/kg). SS31 was administrated for 10 days at dosages of 10 mg/kg per day. Kidney histological changes and level of reactive oxygen species(ROS) were detected. In vitro studies, HK-2 cells were incubated with cisplatin (50 u M) or combimed with SS-31(100 u M), the level of mitochondrial ROS, apoptosis rate and the the expression of NLRP3, Caspase-1 and IL-1β were tested.. Renal tubulointerstitial apoptosis and oxidative stress were significantly increased in CP-AKI mice. Cisplatin caused elevation of serum creatinine (Scr), blood urea nitrogen (BUN) levels and enhanced IL-1β, caspase1 and NLRP3 expression, the electron microscopy examination showed mitochondria cristae swelling, mitochondrial spheres and partial ridge breakdown in renal tubular cell of CP-AKI mice. SS31 treatment could effectively suppress mitochondrial ROS, ameliorate these lesions and decrease the expression of NLRP3, IL-1β and Caspase1. In vitro studies, SS31 could restored the level of mitochondrial ROS and downregulate apoptosis rate in HK-2 cells, moreover, the elevated expression of NLRP3, IL-1β and Caspase-1were restored.. SS31 could protect CP-AKI in mices, which might be due to an anti-oxidative and anti-apoptotic action via regulating mitochondrial ROS-NLRP3 pathway. NLRP3 inflammasome might be considered as a novel therapeutic target of CP-AKI.

Topics: Acute Kidney Injury; Animals; Antineoplastic Agents; Apoptosis; Caspase 1; Cell Line; Cisplatin; Humans; Inflammasomes; Interleukin-1beta; Mice; Mice, Inbred C57BL; Mitochondria; NLR Family, Pyrin Domain-Containing 3 Protein; Oligopeptides; Reactive Oxygen Species; Signal Transduction

Oxidative stress is an important pathological mechanism for acute kidney injury (AKI). SS-31, as a mitochondria-targeted peptide with strong antioxidant activity, is a good candidate for the treatment of AKI. However, an efficient treatment of AKI requires frequent administration of SS-31, which is due to its poor specific biodistribution and low delivery efficiency. To overcome these deficiencies, we designed pH-responsive and AKI-kidney targeted nanopolyplexes (NPs) for effectively delivering SS-31, which is new frontier for formulation of HA and CS. NPs are electrostatically complexed using anionic hyaluronic acid and cationic chitosan as materials, which could increase the accumulation in injured areas and uptake into CD44-overexpressed cells. Electrostatic balance of NPs is broken in low pH environment of lysosomes to allow SS-31 releasing and subsequently targeting to mitochondria to represent therapeutic effect. In vitro studies indicate that NPs exhibited higher antioxidative and antiapoptotic effects as compared with free SS-31. AKI mouse model suggests that NPs have significantly higher therapeutic efficiency than bare SS-31. It was found that NPs had excellent ability to decrease oxidative stress, protect mitochondrial structure, reduce inflammatory response, reduce apoptosis and necrosis of tubular cells after intravenious administration. Overall, the results suggest that the NPs have significant potential to enhance the specific biodistribution and delivery of SS-31, therefore have good effects on reducing oxidative stress and inflammation, preventing tubular apoptosis and necrosis. We believe NPs are effective delivery system for AKI treatment in clinical application.

Topics: Acute Kidney Injury; Animals; Antioxidants; Delayed-Action Preparations; Drug Delivery Systems; Human Umbilical Vein Endothelial Cells; Humans; Hydrogen-Ion Concentration; Mice; Mitochondria; Oligopeptides; Oxidative Stress; Tissue Distribution

The impact of coronary artery stenosis (CAS) on renal injury is unknown. Here we tested whether the existence of CAS, regardless of concurrent atherosclerosis, would induce kidney injury and magnify its susceptibility to damage from coexisting hypertension (HT). Pigs (seven each) were assigned to sham, left-circumflex CAS, renovascular HT, and CAS plus HT groups. Cardiac and nonstenotic kidney functions, circulating and renal inflammatory and oxidative markers, and renal and microvascular remodeling were assessed 10 weeks later. Myocardial perfusion declined distal to CAS. Systemic levels of PGF2-α isoprostane, a marker of oxidative stress, increased in CAS and CAS plus HT, whereas single-kidney blood flow responses to acetylcholine were significantly blunted only in CAS plus HT compared with sham, HT, and CAS, indicating renovascular endothelial dysfunction. Tissue expression of inflammatory and oxidative markers were elevated in the CAS pig kidney, and further magnified in CAS plus HT, whereas angiogenic factor expression was decreased. Bendavia, a mitochondria-targeted peptide, decreased oxidative stress and improved renal function and structure in CAS. Furthermore, CAS and HT synergistically amplified glomerulosclerosis and renal fibrosis. Thus, mild myocardial ischemia, independent of systemic atherosclerosis, induced renal injury, possibly mediated by increased oxidative stress. Superimposed HT aggravates renal inflammation and endothelial dysfunction caused by CAS, and synergistically promotes kidney fibrosis, providing impetus to preserve cardiac integrity in order to protect the kidney.

Topics: Acetylcholine; Acute Kidney Injury; Animals; Antioxidants; Arterial Pressure; Coronary Angiography; Coronary Stenosis; Coronary Vessels; Dinoprost; Endothelium; Female; Fibrosis; Glomerular Filtration Rate; Hypertension, Renovascular; Kidney; Oligopeptides; Oxidative Stress; Renal Circulation; Stroke Volume; Swine; Transforming Growth Factor beta1

Microvascular rarefaction, or loss of microvascular density, is increasingly implicated in the progression from acute ischemic kidney injury to chronic kidney disease. Microvascular dropout results in chronic tissue hypoxia, interstitial inflammation, and fibrosis. There is currently no therapeutic intervention for microvascular rarefaction. We hypothesize that capillary dropout begins with ischemic damage to endothelial mitochondria due to cardiolipin peroxidation, resulting in loss of cristae and the failure to regenerate ATP upon reperfusion. SS-31 is a cell-permeable peptide that targets the inner mitochondrial membrane and binds selectively to cardiolipin. It was recently shown to inhibit cardiolipin peroxidation by cytochrome c peroxidase activity, and it has been shown to protect mitochondrial cristae in proximal tubular cells during ischemia, and accelerated ATP recovery upon reperfusion. We found mitochondrial swelling and loss of cristae membranes in endothelial and medullary tubular epithelial cells after 45-min ischemia in the rat. The loss of cristae membranes limited the ability of these cells to regenerate ATP upon reperfusion and led to loss of vascular integrity and to tubular cell swelling. SS-31 prevented mitochondria swelling and protected cristae membranes in both endothelial and epithelial cells. By minimizing endothelial and epithelial cell injury, SS-31 prevented "no-reflow" after ischemia and significantly reduced the loss of peritubular capillaries and cortical arterioles, interstitial inflammation, and fibrosis at 4 wk after ischemia. These results suggest that mitochondria protection represents an upstream target for pharmacological intervention in microvascular rarefaction and fibrosis.

Topics: Acute Kidney Injury; Adenosine Triphosphate; Animals; Cardiolipins; Cytoprotection; Disease Models, Animal; Disease Progression; Endothelial Cells; Energy Metabolism; Fibrosis; Kidney; Male; Microvessels; Mitochondria; Mitochondrial Membranes; Mitochondrial Swelling; Nephritis; Oligopeptides; Rats; Rats, Sprague-Dawley; Recovery of Function; Renal Insufficiency, Chronic; Reperfusion Injury; Time Factors

The objective of this study is to evaluate the effect and mechanism of mitochondria-targeted peptides (MTP131 and SPI20) on contrast-induced acute kidney injury (CI-AKI) in rats with hypercholesterolemia.. Forty SD rats were randomly divided into normal diet group (NN, n = 8) and high cholesterol supplemented dietary group (HN, n = 32). At the end of 8 weeks, the group HN was divided into four subgroups. All Rats were given injection of either diatrizoate (10 mL/kg) or equal volume of normal saline, the rats pretreated with MTP131 or SPI20 were given injection with MTP131 or SPI 20 (3 mg/kg) by peritoneal cavity for 3 times. Blood, urine and renal tissue samples were prepared to determine biochemical parameters. The renal pathological changes were evaluated by hematoxylin and eosin staining and scored semiquantitatively, The protein expression of renal NOX4 was also measured by Western blotting.. In diatrizoate-injected rats, Serum creatinine (Scr), fractional excretion of sodium (FeNa%), fractional excretion of potassium (FeK%), pathological scores, renal malondialdehyde (MDA) content, the NADPH oxidase activity and the expression of NOX4 in kidney tissue were significantly increased (p < 0.01). In the groups pretreated with MTP131 or SPI20, the levels of Scr, FeNa%, FeK%, MDA content and NADPH oxidase activity in renal tissue decreased (p < 0.01), the levels of renal super oxygen dehydrogenises and ATPase activity increased (p < 0.01). The renal injuries induced by contrast media (CM) were alleviated.. MTP131 and SPI20 might protect acute kidney injury induced by CM in rats with hypercholesterolemia.

Topics: Acute Kidney Injury; Animals; Contrast Media; Diatrizoate; Disease Models, Animal; Hypercholesterolemia; Male; Oligopeptides; Rats; Rats, Sprague-Dawley

The burst of reactive oxygen species (ROS) during reperfusion of ischemic tissues can trigger the opening of the mitochondrial permeability transition (MPT) pore, resulting in mitochondrial depolarization, decreased ATP synthesis, and increased ROS production. Rapid recovery of ATP upon reperfusion is essential for survival of tubular cells, and inhibition of oxidative damage can limit inflammation. SS-31 is a mitochondria-targeted tetrapeptide that can scavenge mitochondrial ROS and inhibit MPT, suggesting that it may protect against ischemic renal injury. Here, in a rat model of ischemia-reperfusion (IR) injury, treatment with SS-31 protected mitochondrial structure and respiration during early reperfusion, accelerated recovery of ATP, reduced apoptosis and necrosis of tubular cells, and abrogated tubular dysfunction. In addition, SS-31 reduced medullary vascular congestion, decreased IR-mediated oxidative stress and the inflammatory response, and accelerated the proliferation of surviving tubular cells as early as 1 day after reperfusion. In summary, these results support MPT as an upstream target for pharmacologic intervention in IR injury and support early protection of mitochondrial function as a therapeutic maneuver to prevent tubular apoptosis and necrosis, reduce oxidative stress, and reduce inflammation. SS-31 holds promise for the prevention and treatment of acute kidney injury.

Topics: Acute Kidney Injury; Adenosine Triphosphate; Animals; Antioxidants; Apoptosis; Kidney Tubules; Male; Mitochondria; Mitochondrial Membrane Transport Proteins; Mitochondrial Permeability Transition Pore; Models, Animal; Oligopeptides; Oxidative Stress; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Regeneration; Reperfusion Injury

Topics: Acute Kidney Injury; Adenosine Triphosphate; Animals; Antioxidants; Apoptosis; Electron Transport; Mitochondria; Models, Animal; Oligopeptides; Rats; Reperfusion Injury