Acute Kidney Injury and Progression of Diabetic Kidney Disease
2018; Elsevier BV; Volume: 25; Issue: 2 Linguagem: Inglês
10.1053/j.ackd.2017.12.005
ISSN1548-5609
AutoresSamuel Mon-Wei Yu, Joseph V. Bonventre,
Tópico(s)Biomedical Research and Pathophysiology
ResumoDiabetic kidney disease, commonly termed diabetic nephropathy (DN), is the most common cause of end-stage kidney disease (ESKD) worldwide. The characteristic histopathology of DN includes glomerular basement membrane thickening, mesangial expansion, nodular glomerular sclerosis, and tubulointerstitial fibrosis. Diabetes is associated with a number of metabolic derangements, such as reactive oxygen species overproduction, hypoxic state, mitochondrial dysfunction, and inflammation. In the past few decades, our knowledge of DN has advanced considerably although much needs to be learned. The traditional paradigm of glomerulus-centered pathophysiology has expanded to the tubule-interstitium, the immune response and inflammation. Biomarkers of proximal tubule injury have been shown to correlate with DN progression, independent of traditional glomerular injury biomarkers such as albuminuria. In this review, we summarize mechanisms of increased susceptibility to acute kidney injury in diabetes mellitus and the roles played by many kidney cell types to facilitate maladaptive responses leading to chronic and end-stage kidney disease. Diabetic kidney disease, commonly termed diabetic nephropathy (DN), is the most common cause of end-stage kidney disease (ESKD) worldwide. The characteristic histopathology of DN includes glomerular basement membrane thickening, mesangial expansion, nodular glomerular sclerosis, and tubulointerstitial fibrosis. Diabetes is associated with a number of metabolic derangements, such as reactive oxygen species overproduction, hypoxic state, mitochondrial dysfunction, and inflammation. In the past few decades, our knowledge of DN has advanced considerably although much needs to be learned. The traditional paradigm of glomerulus-centered pathophysiology has expanded to the tubule-interstitium, the immune response and inflammation. Biomarkers of proximal tubule injury have been shown to correlate with DN progression, independent of traditional glomerular injury biomarkers such as albuminuria. In this review, we summarize mechanisms of increased susceptibility to acute kidney injury in diabetes mellitus and the roles played by many kidney cell types to facilitate maladaptive responses leading to chronic and end-stage kidney disease. Clinical Summary•Multiple clinical studies have shown diabetes mellitus is an independent risk factor for the development of acute kidney injury.•Sustained or uncontrolled hyperglycemia produces proximal tubule and podocyte damage via a host of metabolic stressors.•The onset of albuminuria signifies a critical level of podocyte loss and disruption of the glomerular filtration barrier. Although many treatments have been targeted at improving renal outcomes in clinical trials, only the blockade of the renin-angiotensin-aldosterone system has proven utility. •Multiple clinical studies have shown diabetes mellitus is an independent risk factor for the development of acute kidney injury.•Sustained or uncontrolled hyperglycemia produces proximal tubule and podocyte damage via a host of metabolic stressors.•The onset of albuminuria signifies a critical level of podocyte loss and disruption of the glomerular filtration barrier. Although many treatments have been targeted at improving renal outcomes in clinical trials, only the blockade of the renin-angiotensin-aldosterone system has proven utility. According to the National Diabetes Fact Sheet (www.cdc.gov), diabetes mellitus (DM) was the 7th leading cause of death in the United States in 2013, and more than 20% of health care expenses were spent on patients with diabetes. Long-term complications derived from diabetes include both macrovascular and microvascular diseases. Diabetic nephropathy (DN), or diabetic kidney disease, is one of the main microvascular complications. After adjustment for age, sex, and race, diabetes remains the most common cause leading to ESRD in the United States.1Saran R. Robinson B. Abbott K.C. et al.US renal data system 2016 annual data report: epidemiology of kidney disease in the United States.Am J Kidney Dis. 2017; 69: A7-A8Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar Although the number of major complications from diabetes has substantially declined in the United States, the smallest decline was in ESRD.2Gregg E.W. Li Y. Wang J. et al.Changes in diabetes-related complications in the United States, 1990-2010.N Engl J Med. 2014; 370: 1514-1523Crossref PubMed Scopus (474) Google Scholar DN is characterized by glomerular basement membrane thickening, mesangial expansion, nodular glomerular sclerosis, and tubulointerstitial fibrosis.3Badal S.S. Danesh F.R. New insights into molecular mechanisms of diabetic kidney disease.Am J Kidney Dis. 2014; 63: S63-S83Abstract Full Text Full Text PDF PubMed Google Scholar While DN in individuals with diabetes is common, it is important to recognize that not all patients with diabetes and impaired kidney function have DN with its characteristic pathological features as the cause of their kidney dysfunction, and the kidney pathology, if obtained, varies among patients.4Bojestig M. Arnqvist H.J. Hermansson G. Karlberg B.E. Ludvigsson J. Declining incidence of nephropathy in insulin-dependent diabetes mellitus.N Engl J Med. 1994; 330: 15-18Crossref PubMed Scopus (372) Google Scholar, 5Hovind P. Tarnow L. Rossing K. et al.Decreasing incidence of severe diabetic microangiopathy in type 1 diabetes.Diabetes Care. 2003; 26: 1258-1264Crossref PubMed Scopus (257) Google Scholar, 6Stout L.C. Kumar S. Whorton E.B. Insudative lesions–their pathogenesis and association with glomerular obsolescence in diabetes: a dynamic hypothesis based on single views of advancing human diabetic nephropathy.Hum Pathol. 1994; 25: 1213-1227Abstract Full Text PDF PubMed Scopus (0) Google Scholar, 7Nakagawa T. Tanabe K. Croker B.P. et al.Endothelial dysfunction as a potential contributor in diabetic nephropathy.Nat Rev Nephrol. 2011; 7: 36-44Crossref PubMed Scopus (86) Google Scholar, 8Fioretto P. Stehouwer C.D. Mauer M. et al.Heterogeneous nature of microalbuminuria in NIDDM: studies of endothelial function and renal structure.Diabetologia. 1998; 41: 233-236Crossref PubMed Scopus (0) Google Scholar, 9Rossing P. The changing epidemiology of diabetic microangiopathy in type 1 diabetes.Diabetologia. 2005; 48: 1439-1444Crossref PubMed Scopus (66) Google Scholar When we refer to DN in this article, we refer to patterns of injury that are consistent with those described as characteristic of nephropathy associated with diabetes without other contributors. Multiple studies have shown that diabetes alone is an independent risk factor for acute kidney injury (AKI).1Saran R. Robinson B. Abbott K.C. et al.US renal data system 2016 annual data report: epidemiology of kidney disease in the United States.Am J Kidney Dis. 2017; 69: A7-A8Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 10Waikar S.S. Liu K.D. Chertow G.M. Diagnosis, epidemiology and outcomes of acute kidney injury.Clin J Am Soc Nephrol. 2008; 3: 844-861Crossref PubMed Scopus (258) Google Scholar, 11James M.T. Grams M.E. Woodward M. et al.A meta-analysis of the association of estimated GFR, albuminuria, diabetes mellitus, and hypertension with acute kidney injury.Am J Kidney Dis. 2015; 66: 602-612Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar The incidence of AKI was found to be higher in diabetic patients undergoing surgery,12Mehta R.H. Grab J.D. O'Brien S.M. et al.Bedside tool for predicting the risk of postoperative dialysis in patients undergoing cardiac surgery.Circulation. 2006; 114 (quiz 2208): 2208-2216Crossref PubMed Scopus (251) Google Scholar, 13Kheterpal S. Tremper K.K. Heung M. et al.Development and validation of an acute kidney injury risk index for patients undergoing general surgery: results from a national data set.Anesthesiology. 2009; 110: 505-515Crossref PubMed Scopus (210) Google Scholar, 14Parolari A. Pesce L.L. Pacini D. et al.Risk factors for perioperative acute kidney injury after adult cardiac surgery: role of perioperative management.Ann Thorac Surg. 2012; 93: 584-591Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 15Ko B. Garcia S. Mithani S. Tholakanahalli V. Adabag S. Risk of acute kidney injury in patients who undergo coronary angiography and cardiac surgery in close succession.Eur Heart J. 2012; 33: 2065-2070Crossref PubMed Scopus (32) Google Scholar, 16Hertzberg D. Sartipy U. Holzmann M.J. Type 1 and type 2 diabetes mellitus and risk of acute kidney injury after coronary artery bypass grafting.Am Heart J. 2015; 170: 895-902Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar taking certain medications,17Oliveira J.F. Silva C.A. Barbieri C.D. Oliveira G.M. Zanetta D.M. Burdmann E.A. Prevalence and risk factors for aminoglycoside nephrotoxicity in intensive care units.Antimicrob Agents Chemother. 2009; 53: 2887-2891Crossref PubMed Scopus (57) Google Scholar with sepsis/septic shock,18Venot M. Weis L. Clec'h C. et al.Acute kidney injury in severe sepsis and septic shock in patients with and without diabetes mellitus: a multicenter study.PLoS One. 2015; 10: e0127411Crossref PubMed Google Scholar and even without precipitating events.19Girman C.J. Kou T.D. Brodovicz K. et al.Risk of acute renal failure in patients with Type 2 diabetes mellitus.Diabet Med. 2012; 29: 614-621Crossref PubMed Scopus (0) Google Scholar, 20Mittalhenkle A. Stehman-Breen C.O. Shlipak M.G. et al.Cardiovascular risk factors and incident acute renal failure in older adults: the cardiovascular health study.Clin J Am Soc Nephrol. 2008; 3: 450-456Crossref PubMed Scopus (0) Google Scholar Kidney insults resulting in tissue injury, including acute tubular injury, may affect kidney function and the development of chronic functional impairment in diabetic patients, owing to the fact that the subsequent maladaptive recovery fails to fully reverse the insults.21Basile D.P. Bonventre J.V. Mehta R. et al.Progression after AKI: understanding maladaptive repair processes to predict and identify therapeutic treatments.J Am Soc Nephrol. 2016; 27: 687-697Crossref PubMed Google Scholar, 22Yang L. Besschetnova T.Y. Brooks C.R. Shah J.V. Bonventre J.V. Epithelial cell cycle arrest in G2/M mediates kidney fibrosis after injury.Nat Med. 2010; 16 (531p following 143): 535-543Crossref PubMed Scopus (413) Google Scholar There is, in general, a strong association between AKI and development of chronic kidney disease (CKD) and ESRD.23James M.T. Ghali W.A. Knudtson M.L. et al.Associations between acute kidney injury and cardiovascular and renal outcomes after coronary angiography.Circulation. 2011; 123: 409-416Crossref PubMed Scopus (162) Google Scholar, 24Chew S.T. Ng R.R. Liu W. Chow K.Y. Ti L.K. Acute kidney injury increases the risk of end-stage renal disease after cardiac surgery in an Asian population: a prospective cohort study.BMC Nephrol. 2017; 18: 60Crossref PubMed Scopus (0) Google Scholar, 25Hsu C.Y. Chertow G.M. McCulloch C.E. Fan D. Ordonez J.D. Go A.S. Nonrecovery of kidney function and death after acute on chronic renal failure.Clin J Am Soc Nephrol. 2009; 4: 891-898Crossref PubMed Scopus (204) Google Scholar, 26Ishani A. Nelson D. Clothier B. et al.The magnitude of acute serum creatinine increase after cardiac surgery and the risk of chronic kidney disease, progression of kidney disease, and death.Arch Intern Med. 2011; 171: 226-233Crossref PubMed Scopus (173) Google Scholar Thakar et al. demonstrated, in a cohort of 4082 patients with diabetes, single or repetitive episodes of AKI significantly increases the risk of developing advanced CKD.27Thakar C.V. Christianson A. Himmelfarb J. Leonard A.C. Acute kidney injury episodes and chronic kidney disease risk in diabetes mellitus.Clin J Am Soc Nephrol. 2011; 6: 2567-2572Crossref PubMed Scopus (145) Google Scholar Subsequently, a large prospective study further confirmed that AKI itself can also predict major adverse outcomes including doubling of serum creatinine or ESRD in patients with diabetes.28Monseu M. Gand E. Saulnier P.J. et al.Acute kidney injury predicts major adverse outcomes in diabetes: synergic impact with low glomerular filtration rate and albuminuria.Diabetes Care. 2015; 38: 2333-2340Crossref PubMed Scopus (7) Google Scholar In the past few decades, the knowledge of the impact of DN has expanded beyond the glomerulus (podocyte) to other cell types. In this review, we will discuss the pathophysiology of increased susceptibility to AKI in diabetes and the impact of AKI in diabetes on various kidney cell types, each of which can play a role in injury and maladaptive repair (Fig 1). Furthermore, we discuss how repair after injury might be particularly maladaptive given the diabetic milieu and underlying chronic diabetic changes in the kidney. Glomerular endothelial cells are highly fenestrated cells that carry a thick layer of negatively charged glycocalyx as a component of the glomerular filtration barrier (GFB).29Haraldsson B. Nystrom J. Deen W.M. Properties of the glomerular barrier and mechanisms of proteinuria.Physiol Rev. 2008; 88: 451-487Crossref PubMed Scopus (409) Google Scholar Dysfunction of endothelial cells is one of the key mechanisms in DN, and this dysfunction involves different parts of the kidney including interstitial peritubular capillary vessels and the glomerular afferent and efferent arterioles.30Reidy K. Kang H.M. Hostetter T. Susztak K. Molecular mechanisms of diabetic kidney disease.J Clin Invest. 2014; 124: 2333-2340Crossref PubMed Scopus (138) Google Scholar, 31Xu J. Zou M.H. Molecular insights and therapeutic targets for diabetic endothelial dysfunction.Circulation. 2009; 120: 1266-1286Crossref PubMed Scopus (165) Google Scholar, 32Advani A. Gilbert R.E. The endothelium in diabetic nephropathy.Semin Nephrol. 2012; 32: 199-207Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar Nitric oxide (NO), an endothelium-derived relaxation factor produced by endothelial nitric oxide synthase (eNOS), is known to be reduced in diabetic kidneys. In normal physiology, NO dilates both the afferent and efferent arterioles, regulates the activity of sympathetic tone in the kidneys, and modulates sodium homeostasis.33Tessari P. Nitric oxide in the normal kidney and in patients with diabetic nephropathy.J Nephrol. 2015; 28: 257-268Crossref PubMed Scopus (11) Google Scholar In advanced DN, although the expression of eNOS is upregulated, the production of NO is decreased due to the “uncoupling” of the synthase.34Goligorsky M.S. Chen J. Brodsky S. Workshop: endothelial cell dysfunction leading to diabetic nephropathy : focus on nitric oxide.Hypertension. 2001; 37: 744-748Crossref PubMed Google Scholar Insulin resistance can also inhibit insulin receptor signaling leading to the reduction of NO synthesis.35Artunc F. Schleicher E. Weigert C. Fritsche A. Stefan N. Haring H.U. The impact of insulin resistance on the kidney and vasculature.Nat Rev Nephrol. 2016; 12: 721-737Crossref PubMed Scopus (16) Google Scholar Genetic polymorphisms causing reduced production of NO were reported to accelerate the progression of DN.36Zanchi A. Moczulski D.K. Hanna L.S. Wantman M. Warram J.H. Krolewski A.S. Risk of advanced diabetic nephropathy in type 1 diabetes is associated with endothelial nitric oxide synthase gene polymorphism.Kidney Int. 2000; 57: 405-413Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 37Ezzidi I. Mtiraoui N. Mohamed M.B. Mahjoub T. Kacem M. Almawi W.Y. Association of endothelial nitric oxide synthase Glu298Asp, 4b/a, and -786T>C gene variants with diabetic nephropathy.J Diabetes Complications. 2008; 22: 331-338Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 38Ahluwalia T.S. Ahuja M. Rai T.S. et al.Endothelial nitric oxide synthase gene haplotypes and diabetic nephropathy among Asian Indians.Mol Cell Biochem. 2008; 314: 9-17Crossref PubMed Scopus (43) Google Scholar Altogether, this disturbed NO metabolism in diabetes renders the kidney vasculature more sensitive to stimuli leading to vasoconstriction. Furthermore, the level of vasoactive hormone, endothelin-1 (ET-1), is significantly elevated in DN and makes the vascular resistance even worse.39Hargrove G.M. Dufresne J. Whiteside C. Muruve D.A. Wong N.C. Diabetes mellitus increases endothelin-1 gene transcription in rat kidney.Kidney Int. 2000; 58: 1534-1545Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar Increased kidney resistive indices and sensitivity to vasoconstrictors, such as adenosine, has been found in animal models,40Pflueger A.C. Schenk F. Osswald H. Increased sensitivity of the renal vasculature to adenosine in streptozotocin-induced diabetes mellitus rats.Am J Physiol. 1995; 269: F529-F535PubMed Google Scholar, 41Ishimura E. Nishizawa Y. Kawagishi T. et al.Intrarenal hemodynamic abnormalities in diabetic nephropathy measured by duplex Doppler sonography.Kidney Int. 1997; 51: 1920-1927Abstract Full Text PDF PubMed Google Scholar and also in patients with both metabolic syndrome and type 2 DM.42Buscemi S. Verga S. Batsis J.A. et al.Intra-renal hemodynamics and carotid intima-media thickness in the metabolic syndrome.Diabetes Res Clin Pract. 2009; 86: 177-185Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar These phenomena can explain why DN is a known risk factor for contrast-induced AKI (CIAKI), where vasoconstriction plays an important role leading to ischemic reperfusion injury (IRI), one of the most common causes of AKI.43Calvin A.D. Misra S. Pflueger A. Contrast-induced acute kidney injury and diabetic nephropathy.Nat Rev Nephrol. 2010; 6: 679-688Crossref PubMed Scopus (0) Google Scholar Several potential therapeutic agents against CIAKI have been investigated in patients. These include vasodilators (calcium channel blockers,44Cacoub P. Deray G. Baumelou A. Jacobs C. No evidence for protective effects of nifedipine against radiocontrast-induced acute renal failure.Clin Nephrol. 1988; 29: 215-216PubMed Google Scholar, 45Khoury Z. Schlicht J.R. Como J. et al.The effect of prophylactic nifedipine on renal function in patients administered contrast media.Pharmacotherapy. 1995; 15: 59-65PubMed Google Scholar, 46Madsen J.K. Jensen J.W. Sandermann J. et al.Effect of nitrendipine on renal function and on hormonal parameters after intravascular iopromide.Acta Radiol. 1998; 39: 375-380Crossref PubMed Google Scholar dopamine47Stone G.W. McCullough P.A. Tumlin J.A. et al.Fenoldopam mesylate for the prevention of contrast-induced nephropathy: a randomized controlled trial.JAMA. 2003; 290: 2284-2291Crossref PubMed Scopus (0) Google Scholar), sodium bicarbonate,48Brar S.S. Shen A.Y. Jorgensen M.B. et al.Sodium bicarbonate vs sodium chloride for the prevention of contrast medium-induced nephropathy in patients undergoing coronary angiography: a randomized trial.JAMA. 2008; 300: 1038-1046Crossref PubMed Scopus (240) Google Scholar, 49Maioli M. Toso A. Leoncini M. et al.Sodium bicarbonate versus saline for the prevention of contrast-induced nephropathy in patients with renal dysfunction undergoing coronary angiography or intervention.J Am Coll Cardiol. 2008; 52: 599-604Crossref PubMed Scopus (0) Google Scholar, 50Vasheghani-Farahani A. Sadigh G. Kassaian S.E. et al.Sodium bicarbonate in preventing contrast nephropathy in patients at risk for volume overload: a randomized controlled trial.J Nephrol. 2010; 23: 216-223PubMed Google Scholar, 51Zoungas S. Ninomiya T. Huxley R. et al.Systematic review: sodium bicarbonate treatment regimens for the prevention of contrast-induced nephropathy.Ann Intern Med. 2009; 151: 631-638Crossref PubMed Google Scholar N-acetylcysteine,52Tepel M. van der Giet M. Schwarzfeld C. Laufer U. Liermann D. Zidek W. Prevention of radiographic-contrast-agent-induced reductions in renal function by acetylcysteine.N Engl J Med. 2000; 343: 180-184Crossref PubMed Scopus (0) Google Scholar, 53Fishbane S. N-acetylcysteine in the prevention of contrast-induced nephropathy.Clin J Am Soc Nephrol. 2008; 3: 281-287Crossref PubMed Scopus (78) Google Scholar and statins.54Khanal S. Attallah N. Smith D.E. et al.Statin therapy reduces contrast-induced nephropathy: an analysis of contemporary percutaneous interventions.Am J Med. 2005; 118: 843-849Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 55Jo S.H. Koo B.K. Park J.S. et al.Prevention of radiocontrast medium-induced nephropathy using short-term high-dose simvastatin in patients with renal insufficiency undergoing coronary angiography (PROMISS) trial–a randomized controlled study.Am Heart J. 2008; 155: 499.e1-499.e8Abstract Full Text Full Text PDF Scopus (0) Google Scholar, 56Toso A. Maioli M. Leoncini M. et al.Usefulness of atorvastatin (80 mg) in prevention of contrast-induced nephropathy in patients with chronic renal disease.Am J Cardiol. 2010; 105: 288-292Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar Unfortunately to date, none of these agents were found to be conclusively beneficial. One recent systemic review suggested that high-dose statin plus hydration with or without N-acetylcysteine might prevent CIAKI, but more trials targeted at specific populations such as DN are required to verify the result.57Su X. Xie X. Liu L. et al.Comparative effectiveness of 12 treatment strategies for preventing contrast-induced acute kidney injury: a systematic review and Bayesian Network meta-analysis.Am J Kidney Dis. 2017; 69: 69-77Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar Besides endothelial cell dysfunction, persistent hyperglycemia can also lead to apoptosis of endothelial cells via NF-κB and c-Jun NH2-terminal pathways,58Ho F.M. Liu S.H. Liau C.S. Huang P.J. Lin-Shiau S.Y. High glucose-induced apoptosis in human endothelial cells is mediated by sequential activations of c-Jun NH(2)-terminal kinase and caspase-3.Circulation. 2000; 101: 2618-2624Crossref PubMed Google Scholar, 59Ho F.M. Lin W.W. Chen B.C. et al.High glucose-induced apoptosis in human vascular endothelial cells is mediated through NF-kappaB and c-Jun NH2-terminal kinase pathway and prevented by PI3K/Akt/eNOS pathway.Cell Signal. 2006; 18: 391-399Crossref PubMed Scopus (0) Google Scholar and interstitial vascular rarefaction has been shown in human DN.60Lindenmeyer M.T. Kretzler M. Boucherot A. et al.Interstitial vascular rarefaction and reduced VEGF-A expression in human diabetic nephropathy.J Am Soc Nephrol. 2007; 18: 1765-1776Crossref PubMed Scopus (0) Google Scholar Vascular rarefaction then leads to significant hypoxia in the kidneys, and the endothelial cell itself responds to chronic hypoxia with apoptosis rather than proliferation.32Advani A. Gilbert R.E. The endothelium in diabetic nephropathy.Semin Nephrol. 2012; 32: 199-207Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar In addition, peritubular capillary changes can be a long-term consequence of AKI,61Kramann R. Tanaka M. Humphreys B.D. Fluorescence microangiography for quantitative assessment of peritubular capillary changes after AKI in mice.J Am Soc Nephrol. 2014; 25: 1924-1931Crossref PubMed Scopus (32) Google Scholar and DN can potentially aggravate this loss of perfusion in the kidneys following AKI. Because oxygen (O2) supply is in high demand in kidneys, decreased O2 supply secondary to vascular rarefaction can compromise the generation of adenosine triphosphate (ATP), which is very important for proximal tubule functions.62Aksu U. Demirci C. Ince C. The pathogenesis of acute kidney injury and the toxic triangle of oxygen, reactive oxygen species and nitric oxide.Contrib Nephrol. 2011; 174: 119-128Crossref PubMed Scopus (43) Google Scholar In addition to impaired O2 delivery, oxidative stress from overproduction of reactive oxygen species (ROS) in proximal tubules can damage the endothelial cells in the diabetic state. For example, Han et al. showed that, in the setting of persistent hyperglycemia, ROS such as H2O2 can be generated by proximal tubule cells via protein kinase C and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, and ROS can directly reduce the level of available NO.63Han H.J. Lee Y.J. Park S.H. Lee J.H. Taub M. High glucose-induced oxidative stress inhibits Na+/glucose cotransporter activity in renal proximal tubule cells.Am J Physiol Ren Physiol. 2005; 288: F988-F996Crossref PubMed Scopus (87) Google Scholar Excessive oxidative stress has been well validated as an important pathway leading to CKD.64Kim J. Seok Y.M. Jung K.J. Park K.M. Reactive oxygen species/oxidative stress contributes to progression of kidney fibrosis following transient ischemic injury in mice.Am J Physiol Ren Physiol. 2009; 297: F461-F470Crossref PubMed Scopus (0) Google Scholar, 65Basile D.P. Leonard E.C. Beal A.G. Schleuter D. Friedrich J. Persistent oxidative stress following renal ischemia-reperfusion injury increases ANG II hemodynamic and fibrotic activity.Am J Physiol Ren Physiol. 2012; 302: F1494-F1502Crossref PubMed Scopus (0) Google Scholar Sustained integrity between endothelial cells and pericytes is essential for the stabilization of blood vessels.66Diaz-Flores L. Gutierrez R. Madrid J.F. et al.Pericytes. Morphofunction, interactions and pathology in a quiescent and activated mesenchymal cell niche.Histol Histopathol. 2009; 24: 909-969PubMed Google Scholar, 67Kida Y. Ieronimakis N. Schrimpf C. Reyes M. Duffield J.S. EphrinB2 reverse signaling protects against capillary rarefaction and fibrosis after kidney injury.J Am Soc Nephrol. 2013; 24: 559-572Crossref PubMed Scopus (46) Google Scholar After AKI, the transformation of pericytes to myofibroblasts leads to a series of fibrotic responses,68Zuk A. Bonventre J.V. Acute kidney injury.Annu Rev Med. 2016; 67: 293-307Crossref PubMed Scopus (57) Google Scholar and pericyte detachment from the endothelial cells can also trigger tubular injury and peritubular capillary rarefaction.69Kramann R. Wongboonsin J. Chang-Panesso M. Machado F.G. Humphreys B.D. Gli1+ pericyte loss induces capillary rarefaction and proximal tubular injury.J Am Soc Nephrol. 2017; 28: 776-784Crossref PubMed Scopus (11) Google Scholar Given damaged endothelial cells due to DN, the loss of endothelial-pericyte interaction will facilitate fibrosis and eventually CKD. Therapy targeted to pericyte differentiation has been discussed as a potential therapeutic option for DN, but more studies are required to confirm the role of pericytes in DN.70Humphreys B.D. Targeting pericyte differentiation as a strategy to modulate kidney fibrosis in diabetic nephropathy.Semin Nephrol. 2012; 32: 463-470Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar The cross talk between glomerular endothelium and podocytes has been proposed to play an important role in DN. In the normal glomerulus, vascular endothelial growth factor (VEGF) is mainly produced by podocytes and binds to vascular endothelial growth factor receptor 2 (VEGFR2) located on the endothelium,71Cooper M.E. Vranes D. Youssef S. et al.Increased renal expression of vascular endothelial growth factor (VEGF) and its receptor VEGFR-2 in experimental diabetes.Diabetes. 1999; 48: 2229-2239Crossref PubMed Scopus (0) Google Scholar maintaining vascular formation and differentiation. This paracrine effect is shown to be renoprotective in many different kidney diseases.72Olsson A.K. Dimberg A. Kreuger J. Claesson-Welsh L. VEGF receptor signalling - in control of vascular function.Nat Rev Mol Cell Biol. 2006; 7: 359-371Crossref PubMed Scopus (1744) Google Scholar Specific deletion of VEGF in non-diabetic mouse podocytes can lead to kidney disease characterized by proteinuria and endotheliosis.73Eremina V. Sood M. Haigh J. et al.Glomerular-specific alterations of VEGF-A expression lead to distinct congenital and acquired renal diseases.J Clin Invest. 2003; 111: 707-716Crossref PubMed Google Scholar By contrast, increased levels of VEGF and VEGFR have been reported to aggravate DN71Cooper M.E. Vranes D. Youssef S. et al.Increased renal expression of vascular endothelial growth factor (VEGF) and its receptor VEGFR-2 in experimental diabetes.Diabetes. 1999; 48: 2229-2239Crossref PubMed Scopus (0) Google Scholar, 74Tsuchida K. Makita Z. Yamagishi S. et al.Suppression of transforming growth factor beta and vascular endothelial growth factor in diabetic nephropathy in rats by a novel advanced glycation end product inhibitor, OPB-9195.Diabetologia. 1999; 42: 579-588Crossref PubMed Scopus (0) Google Scholar, 75Saito D. Maeshima Y. Nasu T. et al.Amelioration of renal alterations in obese type 2 diabetic mice by vasohibin-1, a negative feedback regulator of angiogenesis.Am J Physiol Ren Physiol. 2011; 300: F873-F886Crossref PubMed Scopus (27) Google Scholar due to the propagation of a positive feedback loop involving tumor growth factor-ß (TGF-ß), connective tissue growth factor and overproduction of ROS.76Tufro A. Veron D. VEGF and podocytes in diabetic nephropathy.Semin Nephrol. 2012; 32: 385-393Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar Given this observation, multiple studies have attempted to reduce the VEGF signal and demonstrated a favorable outcome.77de Vriese A.S. Tilton R.G. Elger M. Stephan C.C. Kriz W. Lameire N.H. Antibodies against vascular endothelial growth factor improve early renal dysfunction in experimental diabetes.J Am Soc Nephrol. 2001; 12: 993-1000PubMed Google Scholar, 78Sung S.H. Ziyadeh F.N. Wang A. Pyagay P.E. Kanwar Y.S. Chen S. Blockade of vascular endothelial growth factor signaling ameliorates diabetic albuminuria in mice.J Am Soc Nephrol. 2006; 17: 3093-3104Crossref PubMed Scopus (0) Google Scholar, 79Flyvbjerg A. Dagnaes-Hansen F. De Vriese A.S. Schrijvers B.F. Tilton R.G. Rasch R. Amelioration of long-term renal changes in obese type 2 diabetic mice by a neutralizing
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