Comprehensive Physiology Wiley Online Library
For Librarians For Authors Editors About

Renal Vascular Structure and Rarefaction

Alejandro R. Chade

10.1002/cphy.c120012

Source: Volume 3, Issue 2, April 2013

Published online: April 2013

Full Article on Wiley Online Library



Abstract

An intact microcirculation is vital for diffusion of oxygen and nutrients and for removal of toxins of every organ and system in the human body. The functional and/or anatomical loss of microvessels is known as rarefaction, which can compromise the normal organ function and have been suggested as a possible starting point of several diseases. The purpose of this overview is to discuss the potential underlying mechanisms leading to renal microvascular rarefaction, and the potential consequences on renal function and on the progression of renal damage. Although the kidney is a special organ that receives much more blood than its metabolic needs, experimental and clinical evidence indicates that renal microvascular rarefaction is associated to prevalent cardiovascular diseases such as diabetes, hypertension, and atherosclerosis, either as cause or consequence. On the other hand, emerging experimental evidence using progenitor cells or angiogenic cytokines supports the feasibility of therapeutic interventions capable of modifying the progressive nature of microvascular rarefaction in the kidney. This overview will also attempt to discuss the potential renoprotective mechanisms of the therapeutic targeting of the renal microcirculation. © 2013 American Physiological Society. Compr Physiol 3:817‐831, 2013.

Comprehensive Physiology offers downloadable PowerPoint presentations of figures for non-profit, educational use, provided the content is not modified and full credit is given to the author and publication.

Download a PowerPoint presentation of all images


Figure 1. Figure 1.

Schematic illustration describing the general process of microvascular (MV) rarefaction. Changes in the tissue environment and/or metabolic needs may lead to modification in vascular tone and progressive alterations in MV shape and morphology, ultimately resulting in MV irreversible damage and loss. This process accelerates MV damage and may subsequently lead to a feed‐forward deleterious mechanism.
Figure 2. Figure 2.

Section of the human kidney showing the major vessels that supply the blood flow to the kidneys and schematic representation of the microcirculation of the nephron. The figure was reproduced with permission from Guyton and Hall Textbook of Medical Physiology, 12th Edition, 2011, Elsevier.
Figure 3. Figure 3.

Schematic illustration describing the potential mechanisms of renal microvascular (MV) rarefaction and consequences on renal function and structure. Sustained MV endothelial injury (irrespective of the etiology) can lead to an imbalance between factors involved in MV repair, proliferation, and regression, leading to a progressive MV rarefaction that can deteriorate renal hemodynamics, function, and tissue damage. In turn, the progression of renal damage may further stimulate MV damage and loss (red arrows) resulting in a vicious circle. NO, nitric oxide; VEGF, vascular endothelial growth factor; HIF‐1α, hypoxia‐induced factor‐1α.
Figure 4. Figure 4.

Schematic illustration of potential targeted interventions to protect the renal microcirculation, by stimulating MV proliferation, repair, and/or reducing MV damage and loss. Majority of evidence comes from experimental studies. ACE‐I, angiotensin converting enzyme inhibitiors; ARBs, angiotensin receptor blockers; ET‐A, endothelin‐receptor A.
Figure 5. Figure 5.

(A) Representative three‐dimensional micro‐computed tomography (micro‐CT) reconstruction and quantification of the renal MV density and vascular volume fraction, and (B) representative renal protein expression and quantification of angiogenic mediators in normal, renovascular disease (RVD), and RVD + vascular endothelial growth factor (VEGF). Intrarenal VEGF therapy restored the renal expression of VEGF and angiogenic mediators and led to a significant improvement in cortical and medullary MV density compared to untreated RVD. *, P < 0.05 versus normal; †, P < 0.05 versus RVD; #, P = 0.08 versus RVD. Reproduced, with permission, from Chade et al., Am J Physiol Renal Physiol, 302: F1342–F1350, 2012.
Figure 6. Figure 6.

Representative picture showing three‐dimensional micro‐computed tomography (micro‐CT) reconstruction of the renal microvascular (MV) architecture (a), tomographically isolated microvessels (b), and renal cross sections showing MV remodeling (c, ×40) and fibrosis (d, ×20) of a kidney exposed to chronic obstruction of blood flow due to renal artery stenosis. The significant MV rarefaction (a) and remodeling (b, c) correlates with the progression of renal fibrosis (d, curved black arrow). Furthermore, the buildup of renal scarring can promotes changes in MV shape and morphology, as it could also be a source for promoters of MV regression (white arrows).


Figure 1.

Schematic illustration describing the general process of microvascular (MV) rarefaction. Changes in the tissue environment and/or metabolic needs may lead to modification in vascular tone and progressive alterations in MV shape and morphology, ultimately resulting in MV irreversible damage and loss. This process accelerates MV damage and may subsequently lead to a feed‐forward deleterious mechanism.



Figure 2.

Section of the human kidney showing the major vessels that supply the blood flow to the kidneys and schematic representation of the microcirculation of the nephron. The figure was reproduced with permission from Guyton and Hall Textbook of Medical Physiology, 12th Edition, 2011, Elsevier.



Figure 3.

Schematic illustration describing the potential mechanisms of renal microvascular (MV) rarefaction and consequences on renal function and structure. Sustained MV endothelial injury (irrespective of the etiology) can lead to an imbalance between factors involved in MV repair, proliferation, and regression, leading to a progressive MV rarefaction that can deteriorate renal hemodynamics, function, and tissue damage. In turn, the progression of renal damage may further stimulate MV damage and loss (red arrows) resulting in a vicious circle. NO, nitric oxide; VEGF, vascular endothelial growth factor; HIF‐1α, hypoxia‐induced factor‐1α.



Figure 4.

Schematic illustration of potential targeted interventions to protect the renal microcirculation, by stimulating MV proliferation, repair, and/or reducing MV damage and loss. Majority of evidence comes from experimental studies. ACE‐I, angiotensin converting enzyme inhibitiors; ARBs, angiotensin receptor blockers; ET‐A, endothelin‐receptor A.



Figure 5.

(A) Representative three‐dimensional micro‐computed tomography (micro‐CT) reconstruction and quantification of the renal MV density and vascular volume fraction, and (B) representative renal protein expression and quantification of angiogenic mediators in normal, renovascular disease (RVD), and RVD + vascular endothelial growth factor (VEGF). Intrarenal VEGF therapy restored the renal expression of VEGF and angiogenic mediators and led to a significant improvement in cortical and medullary MV density compared to untreated RVD. *, P < 0.05 versus normal; †, P < 0.05 versus RVD; #, P = 0.08 versus RVD. Reproduced, with permission, from Chade et al., Am J Physiol Renal Physiol, 302: F1342–F1350, 2012.



Figure 6.

Representative picture showing three‐dimensional micro‐computed tomography (micro‐CT) reconstruction of the renal microvascular (MV) architecture (a), tomographically isolated microvessels (b), and renal cross sections showing MV remodeling (c, ×40) and fibrosis (d, ×20) of a kidney exposed to chronic obstruction of blood flow due to renal artery stenosis. The significant MV rarefaction (a) and remodeling (b, c) correlates with the progression of renal fibrosis (d, curved black arrow). Furthermore, the buildup of renal scarring can promotes changes in MV shape and morphology, as it could also be a source for promoters of MV regression (white arrows).

References
 1. Antonios TF, Singer DR, Markandu ND, Mortimer PS, MacGregor GA. Structural skin capillary rarefaction in essential hypertension. Hypertension 33: 998‐1001, 1999.
 2. Bakker EN, Buus CL, Spaan JA, Perree J, Ganga A, Rolf TM, Sorop O, Bramsen LH, Mulvany MJ, Vanbavel E. Small artery remodeling depends on tissue‐type transglutaminase. Circ Res 96: 119‐126, 2005.
 3. Balzer KM, Pfeiffer T, Rossbach S, Voiculescu A, Modder U, Godehardt E, Sandmann W. Prospective randomized trial of operative vs interventional treatment for renal artery ostial occlusive disease (RAOOD). J Vasc Surg 49: 667‐674; discussion 674‐665, 2009.
 4. Baricos WH, Cortez SL, Deboisblanc M, Xin S. Transforming growth factor‐beta is a potent inhibitor of extracellular matrix degradation by cultured human mesangial cells. J Am Soc Nephrol 10: 790‐795, 1999.
 5. Basile DP. Rarefaction of peritubular capillaries following ischemic acute renal failure: A potential factor predisposing to progressive nephropathy. Curr Opin Nephrol Hypertens 13: 1‐7, 2004.
 6. Basile DP, Fredrich K, Weihrauch D, Hattan N, Chilian WM. Angiostatin and matrix metalloprotease expression following ischemic acute renal failure. Am J Physiol Renal Physiol 286: F893‐F902, 2004.
 7. Basile DP, Friedrich JL, Spahic J, Knipe N, Mang H, Leonard EC, Changizi‐Ashtiyani S, Bacallao RL, Molitoris BA, Sutton TA. Impaired endothelial proliferation and mesenchymal transition contribute to vascular rarefaction following acute kidney injury. Am J Physiol Renal Physiol 300: F721‐F733, 2011.
 8. Baskin ML, Ard J, Franklin F, Allison DB. Prevalence of obesity in the United States. Obes Rev 6: 5‐7, 2005.
 9. Bates DO, Cui TG, Doughty JM, Winkler M, Sugiono M, Shields JD, Peat D, Gillatt D, Harper SJ. VEGF165b, an inhibitory splice variant of vascular endothelial growth factor, is down‐regulated in renal cell carcinoma. Cancer Res 62: 4123‐4131, 2002.
 10. Battegay EJ, de Miguel LS, Petrimpol M, Humar R. Effects of anti‐hypertensive drugs on vessel rarefaction. Curr Opin Pharmacol 7: 151‐157, 2007.
 11. Bax L, van der Graaf Y, Rabelink AJ, Algra A, Beutler JJ, Mali WP. Influence of atherosclerosis on age‐related changes in renal size and function. Eur J Clin Invest 33: 34‐40, 2003.
 12. Benest AV, Salmon AH, Wang W, Glover CP, Uney J, Harper SJ, Bates DO. VEGF and angiopoietin‐1 stimulate different angiogenic phenotypes that combine to enhance functional neovascularization in adult tissue. Microcirculation 13: 423‐437, 2006.
 13. Biegelsen ES, Loscalzo J. Endothelial function and atherosclerosis. Coron Artery Dis 10: 241‐256, 1999.
 14. Bobik A. The structural basis of hypertension: vascular remodelling, rarefaction and angiogenesis/arteriogenesis. J Hypertens 23: 1473‐1475, 2005.
 15. Bohle A, Mackensen‐Haen S, von Gise H. Significance of tubulointerstitial changes in the renal cortex for the excretory function and concentration ability of the kidney: A morphometric contribution. Am J Nephrol 7: 421‐433, 1987.
 16. Brecker CG, Shustak SR. Contractile proteins in endothelial cells: Comparison of cerebral capillaries with those in heart and skeletal muscle and with liver sinusoids. Circulation 45/46(Suppl II): 87, 1972.
 17. Caballero AE. Endothelial dysfunction in obesity and insulin resistance: A road to diabetes and heart disease. Obes Res 11: 1278‐1289, 2003.
 18. Cambonie G, Comte B, Yzydorczyk C, Ntimbane T, Germain N, Le NL, Pladys P, Gauthier C, Lahaie I, Abran D, Lavoie JC, Nuyt AM. Antenatal antioxidant prevents adult hypertension, vascular dysfunction, and microvascular rarefaction associated with in utero exposure to a low‐protein diet. Am J Physiol Regul Integr Comp Physiol 292: R1236‐R1245, 2007.
 19. Caron A, Desrosiers RR, Langlois S, Beliveau R. Ischemia‐reperfusion injury stimulates gelatinase expression and activity in kidney glomeruli. Can J Physiol Pharmacol 83: 287‐300, 2005.
 20. Chade AR. Renovascular disease, microcirculation, and the progression of renal injury: Role of angiogenesis. Am J Physiol Regul Integr Comp Physiol 300: R783‐R790, 2011.
 21. Chade AR, Bentley MD, Zhu X, Rodriguez‐Porcel M, Niemeyer S, Amores‐Arriaga B, Napoli C, Ritman EL, Lerman A, Lerman LO. Antioxidant intervention prevents renal neovascularization in hypercholesterolemic pigs. J Am Soc Nephrol 15: 1816‐1825, 2004.
 22. Chade AR, Best PJ, Rodriguez‐Porcel M, Herrmann J, Zhu X, Sawamura T, Napoli C, Lerman A, Lerman LO. Endothelin‐1 receptor blockade prevents renal injury in experimental hypercholesterolemia. Kidney Int 64: 962‐969, 2003.
 23. Chade AR, Kelsen S. Renal microvascular disease determines the responses to revascularization in experimental renovascular disease. Circ Cardiovasc Interv 3: 376‐383, 2010.
 24. Chade AR, Kelsen S. Reversal of renal dysfunction by targeted administration of Vegf into the stenotic kidney: A novel potential therapeutic approach. Am J Physiol Renal Physiol 302: F1342‐F1350, 2012.
 25. Chade AR, Krier JD, Galili O, Lerman A, Lerman LO. Role of renal cortical neovascularization in experimental hypercholesterolemia. Hypertension 50: 729‐736, 2007.
 26. Chade AR, Krier JD, Rodriguez‐Porcel M, Breen JF, McKusick MA, Lerman A, Lerman LO. Comparison of acute and chronic antioxidant interventions in experimental renovascular disease. Am J Physiol Renal Physiol 286: F1079‐F1086, 2004.
 27. Chade AR, Krier JD, Textor SC, Lerman A, Lerman LO. Endothelin‐a receptor blockade improves renal microvascular architecture and function in experimental hypercholesterolemia. J Am Soc Nephrol 17: 3394‐3403, 2006.
 28. Chade AR, Lerman A, Lerman LO. Kidney in early atherosclerosis. Hypertension 45: 1042‐1049, 2005.
 29. Chade AR, Mushin OP, Zhu X, Rodriguez‐Porcel M, Grande JP, Textor SC, Lerman A, Lerman LO. Pathways of renal fibrosis and modulation of matrix turnover in experimental hypercholesterolemia. Hypertension 46: 772‐779, 2005.
 30. Chade AR, Rodriguez‐Porcel M, Grande JP, Krier JD, Lerman A, Romero JC, Napoli C, Lerman LO. Distinct renal injury in early atherosclerosis and renovascular disease. Circulation 106: 1165‐1171, 2002.
 31. Chade AR, Rodriguez‐Porcel M, Grande JP, Zhu X, Sica V, Napoli C, Sawamura T, Textor SC, Lerman A, Lerman LO. Mechanisms of renal structural alterations in combined hypercholesterolemia and renal artery stenosis. Arterioscler Thromb Vasc Biol 23: 1295‐1301, 2003.
 32. Chade AR, Rodriguez‐Porcel M, Herrmann J, Krier JD, Zhu X, Lerman A, Lerman LO. Beneficial effects of antioxidant vitamins on the stenotic kidney. Hypertension 42: 605‐612, 2003.
 33. Chade AR, Rodriguez‐Porcel M, Herrmann J, Zhu X, Grande JP, Napoli C, Lerman A, Lerman LO. Antioxidant intervention blunts renal injury in experimental renovascular disease. J Am Soc Nephrol 15: 958‐966, 2004.
 34. Chade AR, Rodriguez‐Porcel M, Rippentrop SJ, Lerman A, Lerman LO. Angiotensin II AT1 receptor blockade improves renal perfusion in hypercholesterolemia. Am J Hypertens 16: 111‐115, 2003.
 35. Chade AR, Zhu X, Lavi R, Krier JD, Pislaru S, Simari RD, Napoli C, Lerman A, Lerman LO. Endothelial progenitor cells restore renal function in chronic experimental renovascular disease. Circulation 119: 547‐557, 2009.
 36. Chade AR, Zhu X, Mushin OP, Napoli C, Lerman A, Lerman LO. Simvastatin promotes angiogenesis and prevents microvascular remodeling in chronic renal ischemia. Faseb J 20: 1706‐1708, 2006.
 37. Chade AR, Zhu XY, Grande JP, Krier JD, Lerman A, Lerman LO. Simvastatin abates development of renal fibrosis in experimental renovascular disease. J Hypertens 26: 1651‐1660, 2008.
 38. Chade AR, Zhu XY, Krier JD, Jordan KL, Textor SC, Grande JP, Lerman A, Lerman LO. Endothelial progenitor cells homing and renal repair in experimental renovascular disease. Stem Cells 28: 1039‐1047, 2010.
 39. Chatziantoniou C, Boffa JJ, Tharaux PL, Flamant M, Ronco P, Dussaule JC. Progression and regression in renal vascular and glomerular fibrosis. Int J Exp Pathol 85: 1‐11, 2004.
 40. Chen F, Tan Z, Dong CY, Chen X, Guo SF. Adeno‐associated virus vectors simultaneously encoding VEGF and angiopoietin‐1 enhances neovascularization in ischemic rabbit hind‐limbs. Acta Pharmacol Sin 28: 493‐502, 2007.
 41. Chen J, Zhang ZG, Li Y, Wang Y, Wang L, Jiang H, Zhang C, Lu M, Katakowski M, Feldkamp CS, Chopp M. Statins induce angiogenesis, neurogenesis, and synaptogenesis after stroke. Ann Neurol 53: 743‐751, 2003.
 42. Chen JW, Hsu NW, Wu TC, Lin SJ, Chang MS. Long‐term angiotensin‐converting enzyme inhibition reduces plasma asymmetric dimethylarginine and improves endothelial nitric oxide bioavailability and coronary microvascular function in patients with syndrome X. Am J Cardiol 90: 974‐982, 2002.
 43. Cheung CM, Chrysochou C, Shurrab AE, Buckley DL, Cowie A, Kalra PA. Effects of renal volume and single‐kidney glomerular filtration rate on renal functional outcome in atherosclerotic renal artery stenosis. Nephrol Dial Transplant 25: 1133‐1140, 2010.
 44. Cowley AW, Jr, Roman RJ, Krieger JE. Pathways linking renal excretion and arterial pressure with vascular structure and function. Clin Exp Pharmacol Physiol 18: 21‐27, 1991.
 45. Davis GE, Senger DR. Extracellular matrix mediates a molecular balance between vascular morphogenesis and regression. Curr Opin Hematol 15: 197‐203, 2008.
 46. de Jongh RT, Serne EH, IJzerman RG, de Vries G, Stehouwer CD. Impaired microvascular function in obesity: implications for obesity‐associated microangiopathy, hypertension, and insulin resistance. Circulation 109: 2529‐2535, 2004.
 47. Denton KM, Anderson WP. Glomerular ultrafiltration in rabbits with superficial glomeruli. Pflugers Arch 419: 235‐242, 1991.
 48. Denton KM, Anderson WP, Sinniah R. Effects of angiotensin II on regional afferent and efferent arteriole dimensions and the glomerular pole. Am J Physiol Regul Integr Comp Physiol 279: R629‐R638, 2000.
 49. Desrosiers RR, Rivard ME, Grundy PE, Annabi B. Decrease in LDL receptor‐related protein expression and function correlates with advanced stages of Wilms tumors. Pediatr Blood Cancer 46: 40‐49, 2006.
 50. Dessapt C, Karalliedde J, Hernandez‐Fuentes M, Martin PP, Maltese G, Dattani N, Atkar R, Viberti G, Gnudi L. Circulating vascular progenitor cells in patients with type 1 diabetes and microalbuminuria. Diabetes Care 33: 875‐877, 2010.
 51. Deuse T, Peter C, Fedak PW, Doyle T, Reichenspurner H, Zimmermann WH, Eschenhagen T, Stein W, Wu JC, Robbins RC, Schrepfer S. Hepatocyte growth factor or vascular endothelial growth factor gene transfer maximizes mesenchymal stem cell‐based myocardial salvage after acute myocardial infarction. Circulation 120: S247‐S254, 2009.
 52. Duncan MR, Frazier KS, Abramson S, Williams S, Klapper H, Huang X, Grotendorst GR. Connective tissue growth factor mediates transforming growth factor beta‐induced collagen synthesis: down‐regulation by cAMP. Faseb J 13: 1774‐1786, 1999.
 53. Dworkin LD, Gong R, Tolbert E, Centracchio J, Yano N, Zanabli AR, Esparza A, Rifai A. Hepatocyte growth factor ameliorates progression of interstitial fibrosis in rats with established renal injury. Kidney Int 65: 409‐419, 2004.
 54. Dworkin LD, Murphy T. Is there any reason to stent atherosclerotic renal artery stenosis? Am J Kidney Dis 56: 259‐263, 2010.
 55. Eirin A, Zhu XY, Urbieta‐Caceres VH, Grande JP, Lerman A, Textor SC, Lerman LO. Persistent kidney dysfunction in swine renal artery stenosis correlates with outer cortical microvascular remodeling. Am J Physiol Renal Physiol 300: F1394‐F1401, 2011.
 56. Endemann DH, Schiffrin EL. Endothelial dysfunction. J Am Soc Nephrol 15: 1983‐1992, 2004.
 57. Feihl F, Liaudet L, Waeber B. The macrocirculation and microcirculation of hypertension. Curr Hypertens Rep 11: 182‐189, 2009.
 58. Fliser D. Perspectives in renal disease progression: The endothelium as a treatment target in chronic kidney disease. J Nephrol 23: 369‐376, 2011.
 59. Futrakul N, Butthep P, Laohareungpanya N, Chaisuriya P, Ratanabanangkoon K. A defective angiogenesis in chronic kidney disease. Ren Fail 30: 215‐217, 2008.
 60. Futrakul N, Futrakul P. Vascular homeostasis and angiogenesis determine therapeutic effectiveness in type 2 diabetes. Int J Vasc Med 2011: 971524, 2011.
 61. Galle J, Quaschning T, Seibold S, Wanner C. Endothelial dysfunction and inflammation: What is the link? Kidney Int Suppl: S45‐S49, 2003.
 62. Gerritsen ME. HGF and VEGF: A dynamic duo. Circ Res 96: 272‐273, 2005.
 63. Giles TD, Sander GE, Nossaman BD, Kadowitz PJ. Impaired vasodilation in the pathogenesis of hypertension: Focus on nitric oxide, endothelial‐derived hyperpolarizing factors, and prostaglandins. J Clin Hypertens (Greenwich) 14: 198‐205, 2012.
 64. Gokce N, Keaney JF, Jr, Hunter LM, Watkins MT, Nedeljkovic ZS, Menzoian JO, Vita JA. Predictive value of noninvasively determined endothelial dysfunction for long‐term cardiovascular events in patients with peripheral vascular disease. J Am Coll Cardiol 41: 1769‐1775, 2003.
 65. Goligorsky MS, Yasuda K, Ratliff B. Dysfunctional endothelial progenitor cells in chronic kidney disease. J Am Soc Nephrol 21: 911‐919, 2010.
 66. Gomes MB, Affonso FS, Cailleaux S, Almeida AL, Pinto LF, Tibirica E. Glucose levels observed in daily clinical practice induce endothelial dysfunction in the rabbit macro‐ and microcirculation. Fundam Clin Pharmacol 18: 339‐346, 2004.
 67. Gomez SI, Warner L, Haas JA, Bolterman RJ, Textor SC, Lerman LO, Romero JC. Increased hypoxia and reduced renal tubular response to furosemide detected by BOLD magnetic resonance imaging in swine renovascular hypertension. Am J Physiol Renal Physiol 297: F981‐F986, 2009.
 68. Graff J, Harder S, Wahl O, Scheuermann EH, Gossmann J. Anti‐inflammatory effects of clopidogrel intake in renal transplant patients: effects on platelet‐leukocyte interactions, platelet CD40 ligand expression, and proinflammatory biomarkers. Clin Pharmacol Ther 78: 468‐476, 2005.
 69. Grande JP. Role of transforming growth factor‐beta in tissue injury and repair. Proc Soc Exp Biol Med 214: 27‐40, 1997.
 70. Greene AS, Tonellato PJ, Lui J, Lombard JH, Cowley AW, Jr. Microvascular rarefaction and tissue vascular resistance in hypertension. Am J Physiol 256: H126‐H131, 1989.
 71. Hall JE. The kidney, hypertension, and obesity. Hypertension 41: 625‐633, 2003.
 72. Hansen KJ, Edwards MS, Craven TE, Cherr GS, Jackson SA, Appel RG, Burke GL, Dean RH. Prevalence of renovascular disease in the elderly: A population‐based study. J Vasc Surg 36: 443‐451, 2002.
 73. Hattori K, Dias S, Heissig B, Hackett NR, Lyden D, Tateno M, Hicklin DJ, Zhu Z, Witte L, Crystal RG, Moore MA, Rafii S. Vascular endothelial growth factor and angiopoietin‐1 stimulate postnatal hematopoiesis by recruitment of vasculogenic and hematopoietic stem cells. J Exp Med 193: 1005‐1014, 2001.
 74. Hayashi S, Morishita R, Nakamura S, Yamamoto K, Moriguchi A, Nagano T, Taiji M, Noguchi H, Matsumoto K, Nakamura T, Higaki J, Ogihara T. Potential role of hepatocyte growth factor, a novel angiogenic growth factor, in peripheral arterial disease: Downregulation of HGF in response to hypoxia in vascular cells. Circulation 100: II301‐II308, 1999.
 75. Hedley AA, Ogden CL, Johnson CL, Carroll MD, Curtin LR, Flegal KM. Prevalence of overweight and obesity among US children, adolescents, and adults, 1999‐2002. JAMA 291: 2847‐2850, 2004.
 76. Henry TD, Rocha‐Singh K, Isner JM, Kereiakes DJ, Giordano FJ, Simons M, Losordo DW, Hendel RC, Bonow RO, Eppler SM, Zioncheck TF, Holmgren EB, McCluskey ER. Intracoronary administration of recombinant human vascular endothelial growth factor to patients with coronary artery disease. Am Heart J 142: 872‐880, 2001.
 77. Hohenstein B, Hausknecht B, Boehmer K, Riess R, Brekken RA, Hugo CP. Local VEGF activity but not VEGF expression is tightly regulated during diabetic nephropathy in man. Kidney Int 69: 1654‐1661, 2006.
 78. Hugo C, Daniel C. Thrombospondin in renal disease. Nephron Exp Nephrol 111: e61‐e66, 2009.
 79. Ichinose K, Maeshima Y, Yamamoto Y, Kitayama H, Takazawa Y, Hirokoshi K, Sugiyama H, Yamasaki Y, Eguchi K, Makino H. Antiangiogenic endostatin peptide ameliorates renal alterations in the early stage of a type 1 diabetic nephropathy model. Diabetes 54: 2891‐2903, 2005.
 80. Iliescu R, Chade AR. Progressive renal vascular proliferation and injury in obese Zucker rats. Microcirculation 17: 250‐258, 2010.
 81. Iliescu R, Fernandez SR, Kelsen S, Maric C, Chade AR. Role of renal microcirculation in experimental renovascular disease. Nephrol Dial Transplant 25: 1079‐1087, 2010.
 82. Inoue T, Okada H, Kobayashi T, Watanabe Y, Kanno Y, Kopp JB, Nishida T, Takigawa M, Ueno M, Nakamura T, Suzuki H. Hepatocyte growth factor counteracts transforming growth factor‐beta1, through attenuation of connective tissue growth factor induction, and prevents renal fibrogenesis in 5/6 nephrectomized mice. Faseb J 17: 268‐270, 2003.
 83. Jesmin S, Zaedi S, Shimojo N, Iemitsu M, Masuzawa K, Yamaguchi N, Mowa CN, Maeda S, Hattori Y, Miyauchi T. Endothelin antagonism normalizes VEGF signaling and cardiac function in STZ‐induced diabetic rat hearts. Am J Physiol Endocrinol Metab 292: E1030‐E1040, 2007.
 84. Josifova T, Schneider U, Henrich PB, and Schrader W. Eye disorders in diabetes: Potential drug targets. Infect Disord Drug Targets 8: 70‐75, 2008.
 85. Kalousova M, Hodkova M, Dusilova‐Sulkova S, Uhrova J, Tesar V, Zima T. Effect of hemodiafiltration on pregnancy‐associated plasma protein A (PAPP‐A) and related parameters. Ren Fail 28: 715‐721, 2006.
 86. Kalra PA, Guo H, Kausz AT, Gilbertson DT, Liu J, Chen SC, Ishani A, Collins AJ, Foley RN. Atherosclerotic renovascular disease in United States patients aged 67 years or older: risk factors, revascularization, and prognosis. Kidney Int 68: 293‐301, 2005.
 87. Kang DH, Anderson S, Kim YG, Mazzalli M, Suga S, Jefferson JA, Gordon KL, Oyama TT, Hughes J, Hugo C, Kerjaschki D, Schreiner GF, Johnson RJ. Impaired angiogenesis in the aging kidney: Vascular endothelial growth factor and thrombospondin‐1 in renal disease. Am J Kidney Dis 37: 601‐611, 2001.
 88. Kang DH, Hughes J, Mazzali M, Schreiner GF, Johnson RJ. Impaired angiogenesis in the remnant kidney model: II. Vascular endothelial growth factor administration reduces renal fibrosis and stabilizes renal function. J Am Soc Nephrol 12: 1448‐1457, 2001.
 89. Kang DH, Kanellis J, Hugo C, Truong L, Anderson S, Kerjaschki D, Schreiner GF, Johnson RJ. Role of the microvascular endothelium in progressive renal disease. J Am Soc Nephrol 13: 806‐816, 2002.
 90. Karihaloo A, Karumanchi SA, Barasch J, Jha V, Nickel CH, Yang J, Grisaru S, Bush KT, Nigam S, Rosenblum ND, Sukhatme VP, Cantley LG. Endostatin regulates branching morphogenesis of renal epithelial cells and ureteric bud. Proc Natl Acad Sci U S A 98: 12509‐12514, 2001.
 91. Kelsen S, Hall JE, Chade AR. Endothelin‐A receptor blockade slows the progression of renal injury in experimental renovascular disease. Am J Physiol Renal Physiol 301: F218‐F225, 2011.
 92. Kistorp C, Chong AY, Gustafsson F, Galatius S, Raymond I, Faber J, Lip GY, Hildebrandt P. Biomarkers of endothelial dysfunction are elevated and related to prognosis in chronic heart failure patients with diabetes but not in those without diabetes. Eur J Heart Fail 10: 380‐387, 2008.
 93. Kitayama H, Maeshima Y, Takazawa Y, Yamamoto Y, Wu Y, Ichinose K, Hirokoshi K, Sugiyama H, Yamasaki Y, Makino H. Regulation of angiogenic factors in angiotensin II infusion model in association with tubulointerstitial injuries. Am J Hypertens 19: 718‐727, 2006.
 94. Ko SH, Cao W, Liu Z. Hypertension management and microvascular insulin resistance in diabetes. Curr Hypertens Rep 12: 243‐251, 2011.
 95. Korn C, Augustin HG. Born to die: Blood vessel regression research coming of age. Circulation 125: 3063‐3065, 2012.
 96. Lee DH, Wolstein JM, Pudasaini B, Plotkin M. INK4a deletion results in improved kidney regeneration and decreased capillary rarefaction after ischemia‐reperfusion injury. Am J Physiol Renal Physiol 302: F183‐F191, 2012.
 97. Lee JS, Kim JM, Kim KL, Jang HS, Shin IS, Jeon ES, Suh W, Byun J, Kim DK. Combined administration of naked DNA vectors encoding VEGF and bFGF enhances tissue perfusion and arteriogenesis in ischemic hindlimb. Biochem Biophys Res Commun 360: 752‐758, 2007.
 98. Lee JS, Song SH, Kim JM, Shin IS, Kim KL, Suh YL, Kim HZ, Koh GY, Byun J, Jeon ES, Suh W, Kim DK. Angiopoietin‐1 prevents hypertension and target organ damage through its interaction with endothelial Tie2 receptor. Cardiovasc Res 78: 572‐580, 2008.
 99. Lee LK, Meyer TW, Pollock AS, Lovett DH. Endothelial cell injury initiates glomerular sclerosis in the rat remnant kidney. J Clin Invest 96: 953‐964, 1995.
 100. Leopold JA, Loscalzo J. Clinical importance of understanding vascular biology. Cardiol Rev 8: 115‐123, 2000.
 101. Lerman LO, Taler SJ, Textor SC, Sheedy PF, II, Stanson AW, Romero JC. Computed tomography‐derived intrarenal blood flow in renovascular and essential hypertension. Kidney Int 49: 846‐854, 1996.
 102. Levy BI, Schiffrin EL, Mourad JJ, Agostini D, Vicaut E, Safar ME, Struijker‐Boudier HA. Impaired tissue perfusion: a pathology common to hypertension, obesity, and diabetes mellitus. Circulation 118: 968‐976, 2008.
 103. Lindenmeyer MT, Kretzler M, Boucherot A, Berra S, Yasuda Y, Henger A, Eichinger F, Gaiser S, Schmid H, Rastaldi MP, Schrier RW, Schlondorff D, Cohen CD. Interstitial vascular rarefaction and reduced VEGF‐A expression in human diabetic nephropathy. J Am Soc Nephrol 18: 1765‐1776, 2007.
 104. Linke A, Recchia F, Zhang X, Hintze TH. Acute and chronic endothelial dysfunction: Implications for the development of heart failure. Heart Fail Rev 8: 87‐97, 2003.
 105. Lohmeier TE, Iliescu R, Liu B, Henegar JR, Maric‐Bilkan C, Irwin ED. Systemic and renal‐specific sympathoinhibition in obesity hypertension. Hypertension 59: 331‐338, 2012.
 106. Lohmeier TE, Warren S, Cunningham JT. Sustained activation of the central baroreceptor pathway in obesity hypertension. Hypertension 42: 96‐102, 2003.
 107. Lorenzen J, David S, Bahlmann FH, de Groot K, Bahlmann E, Kielstein JT, Haller H, Fliser D. Endothelial progenitor cells and cardiovascular events in patients with chronic kidney disease–a prospective follow‐up study. PLoS One 5: e11477, 2010.
 108. Lupia E, Elliot SJ, Lenz O, Zheng F, Hattori M, Striker GE, Striker LJ. IGF‐1 decreases collagen degradation in diabetic NOD mesangial cells: Implications for diabetic nephropathy. Diabetes 48: 1638‐1644, 1999.
 109. Maciel TT, Coutinho EL, Soares D, Achar E, Schor N, Bellini MH. Endostatin, an antiangiogenic protein, is expressed in the unilateral ureteral obstruction mice model. J Nephrol 21: 753‐760, 2008.
 110. Maeshima Y, Makino H. Angiogenesis and chronic kidney disease. Fibrogenesis Tissue Repair 3: 13, 2010.
 111. Makino H, Okada S, Nagumo A, Sugisawa T, Miyamoto Y, Kishimoto I, Kikuchi‐Taura A, Soma T, Taguchi A, Yoshimasa Y. Decreased circulating CD34+ cells are associated with progression of diabetic nephropathy. Diabet Med 26: 171‐173, 2009.
 112. Maric‐Bilkan C, Flynn ER, Chade AR. Microvascular disease precedes the decline in renal function in the streptozotocin‐induced diabetic rat. Am J Physiol Renal Physiol 302: F308‐F315, 2012.
 113. Marin P, Andersson B, Krotkiewski M, Bjorntorp P. Muscle fiber composition and capillary density in women and men with NIDDM. Diabetes Care 17: 382‐386, 1994.
 114. Mayer G. Capillary rarefaction, hypoxia, VEGF and angiogenesis in chronic renal disease. Nephrol Dial Transplant 26: 1132‐1137, 2011.
 115. McLennan SV, Kelly DJ, Schache M, Waltham M, Dy V, Langham RG, Yue DK, Gilbert RE. Advanced glycation end products decrease mesangial cell MMP‐7: A role in matrix accumulation in diabetic nephropathy? Kidney Int 72: 481‐488, 2007.
 116. McLennan SV, Wang XY, Moreno V, Yue DK, Twigg SM. Connective tissue growth factor mediates high glucose effects on matrix degradation through tissue inhibitor of matrix metalloproteinase type 1: Implications for diabetic nephropathy. Endocrinology 145: 5646‐5655, 2004.
 117. Moore MA, Hattori K, Heissig B, Shieh JH, Dias S, Crystal RG, Rafii S. Mobilization of endothelial and hematopoietic stem and progenitor cells by adenovector‐mediated elevation of serum levels of SDF‐1, VEGF, and angiopoietin‐1. Ann N Y Acad Sci 938: 36‐45; discussion 45‐37, 2001.
 118. Nakagawa T, Lan HY, Zhu HJ, Kang DH, Schreiner GF, Johnson RJ. Differential regulation of VEGF by TGF‐beta and hypoxia in rat proximal tubular cells. Am J Physiol Renal Physiol 287: F658‐F664, 2004.
 119. Navar LG, Arendhorst WJ, Pallone TL, Inscho EW, Imig JD, Bell PD. The renal microcirculation. In: Tuma RF, Duran WN, and Ley K, editors. Handbook of Physiology: Microcirculation, San Diego, CA: Elsevier, 2008, pp. 550‐683.
 120. O'Donovan HC, Hickey F, Brazil DP, Kavanagh DH, Oliver N, Martin F, Godson C, Crean J. Connective tissue growth factor antagonizes transforming growth factor‐beta1/Smad signalling in renal mesangial cells. Biochem J 441: 499‐510, 2012.
 121. O'Hare AM, Glidden DV, Fox CS, Hsu CY. High prevalence of peripheral arterial disease in persons with renal insufficiency: results from the National Health and Nutrition Examination Survey 1999‐2000. Circulation 109: 320‐323, 2004.
 122. Olszewska‐Pazdrak B, Hein TW, Olszewska P, Carney DH. Chronic hypoxia attenuates VEGF signaling and angiogenic responses by downregulation of KDR in human endothelial cells. Am J Physiol Cell Physiol 296: C1162‐C1170, 2009.
 123. Paravicini TM Touyz RM. NADPH oxidases, reactive oxygen species, and hypertension: clinical implications and therapeutic possibilities. Diabetes Care 31(Suppl 2): S170‐S180, 2008.
 124. Pasarica M, Sereda OR, Redman LM, Albarado DC, Hymel DT, Roan LE, Rood JC, Burk DH, Smith SR. Reduced adipose tissue oxygenation in human obesity: Evidence for rarefaction, macrophage chemotaxis, and inflammation without an angiogenic response. Diabetes 58: 718‐725, 2009.
 125. Peirce SM, Skalak TC. Microvascular remodeling: a complex continuum spanning angiogenesis to arteriogenesis. Microcirculation 10: 99‐111, 2003.
 126. Pelliccia F, Pasceri V, Cianfrocca C, Vitale C, Pristipino C, Speciale G, Mercuro G, Rosano G. Endothelial progenitor cells in patients with coronary artery disease and left ventricular dysfunction. Coron Artery Dis 20: 303‐308, 2009.
 127. Pessina AC. Target organs of individuals with diabetes caught between arterial stiffness and damage to the microcirculation. J Hypertens Suppl 25: S13‐S18, 2007.
 128. Prewitt RL, Chen, II, Dowell R. Development of microvascular rarefaction in the spontaneously hypertensive rat. Am J Physiol 243: H243‐H251, 1982.
 129. Qi W, Chen X, Poronnik P, Pollock CA. Transforming growth factor‐beta/connective tissue growth factor axis in the kidney. Int J Biochem Cell Biol 40: 9‐13, 2008.
 130. Qi W, Twigg S, Chen X, Polhill TS, Poronnik P, Gilbert RE, Pollock CA. . Am J Physiol Renal Physiol 288: F800‐F809, 2005.
 131. Rabelink TJ, Wijewickrama DC, de Koning EJ. Peritubular endothelium: The Achilles heel of the kidney? Kidney Int 72: 926‐930, 2007.
 132. Raptis AE, Viberti G. Pathogenesis of diabetic nephropathy. Exp Clin Endocrinol Diabetes 109(Suppl 2): S424‐S437, 2001.
 133. Reckelhoff JF, Romero JC. Role of oxidative stress in angiotensin‐induced hypertension. Am J Physiol Regul Integr Comp Physiol 284: R893‐R912, 2003.
 134. Rudnicki M, Perco P, Enrich J, Eder S, Heininger D, Bernthaler A, Wiesinger M, Sarkozi R, Noppert SJ, Schramek H, Mayer B, Oberbauer R, Mayer G. Hypoxia response and VEGF‐A expression in human proximal tubular epithelial cells in stable and progressive renal disease. Lab Invest 89: 337‐346, 2009.
 135. Ryan ST, Koteliansky VE, Gotwals PJ, Lindner V. Transforming growth factor‐beta‐dependent events in vascular remodeling following arterial injury. J Vasc Res 40: 37‐46, 2003.
 136. Rysz J, Banach M, Stolarek RA, Pasnik J, Cialkowska‐Rysz A, Koktysz R, Piechota M, Baj Z. Serum matrix metalloproteinases MMP‐2 and MMP‐9 and metalloproteinase tissue inhibitors TIMP‐1 and TIMP‐2 in diabetic nephropathy. J Nephrol 20: 444‐452, 2007.
 137. Safian RD, Textor SC. Renal‐artery stenosis. N Engl J Med 344: 431‐442, 2001.
 138. Sakurai H, Nigam SK. Transforming growth factor‐beta selectively inhibits branching morphogenesis but not tubulogenesis. Am J Physiol 272: F139‐F146, 1997.
 139. Saleh MA, Boesen EI, Pollock JS, Savin VJ, Pollock DM. Endothelin‐1 increases glomerular permeability and inflammation independent of blood pressure in the rat. Hypertension 56: 942‐949, 2010.
 140. Schindler TH, Cardenas J, Prior JO, Facta AD, Kreissl MC, Zhang XL, Sayre J, Dahlbom M, Licinio J, Schelbert HR. Relationship between increasing body weight, insulin resistance, inflammation, adipocytokine leptin, and coronary circulatory function. J Am Coll Cardiol 47: 1188‐1195, 2006.
 141. Shimizu T, Okamoto H, Chiba S, Matsui Y, Sugawara T, Akino M, Nan J, Kumamoto H, Onozuka H, Mikami T, Kitabatake A. VEGF‐mediated angiogenesis is impaired by angiotensin type 1 receptor blockade in cardiomyopathic hamster hearts. Cardiovasc Res 58: 203‐212, 2003.
 142. Sila‐asna M, Bunyaratvej A, Futrakul P, Futrakul N. Renal microvascular abnormality in chronic kidney disease. Ren Fail 28: 609‐610, 2006.
 143. Stenvinkel P. Endothelial dysfunction and inflammation‐is there a link? Nephrol Dial Transplant 16: 1968‐1971, 2001.
 144. Stenvinkel P. Interactions between inflammation, oxidative stress, and endothelial dysfunction in end‐stage renal disease. J Ren Nutr 13: 144‐148, 2003.
 145. Suh W, Lee JS, Kim KL, Song SH, Koh GY, Kim DK. Angiopoietin‐1 gene therapy attenuates hypertension and target organ damage in nitric oxide synthase inhibited spontaneously hypertensive rats. Korean Circ J 41: 590‐595, 2011.
 146. Takahashi S, Shinya T, Sugiyama A. Angiostatin inhibition of vascular endothelial growth factor‐stimulated nitric oxide production in endothelial cells. J Pharmacol Sci 112: 432‐437, 2010.
 147. Textor SC. Ischemic nephropathy: Where are we now? J Am Soc Nephrol 15: 1974‐1982, 2004.
 148. Textor SC, Wilcox CS. Renal artery stenosis: A common, treatable cause of renal failure? Annu Rev Med 52: 421‐442, 2001.
 149. Urbieta Caceres VH, Syed FA, Lin J, Zhu XY, Jordan KL, Bell CC, Bentley MD, Lerman A, Khosla S, Lerman LO. Age‐dependent renal cortical microvascular loss in female mice. Am J Physiol Endocrinol Metab 302: E979‐E986, 2012.
 150. VanBavel E, Bakker EN, Pistea A, Sorop O, Spaan JA. Mechanics of microvascular remodeling. Clin Hemorheol Microcirc 34: 35‐41, 2006.
 151. Vaziri ND, Ni Z, Oveisi F, Liang K, Pandian R. Enhanced nitric oxide inactivation and protein nitration by reactive oxygen species in renal insufficiency. Hypertension 39: 135‐141, 2002.
 152. Wacker A, Gerhardt H. Endothelial development taking shape. Curr Opin Cell Biol 23: 676‐685, 2011.
 153. Wang D, Iversen J, Wilcox CS, Strandgaard S. Endothelial dysfunction and reduced nitric oxide in resistance arteries in autosomal‐dominant polycystic kidney disease. Kidney Int 64: 1381‐1388, 2003.
 154. Wang R, Xu YJ, Liu XS, Zeng DX, Xiang M. Knockdown of connective tissue growth factor by plasmid‐based short hairpin RNA prevented pulmonary vascular remodeling in cigarette smoke‐exposed rats. Arch Biochem Biophys 508: 93‐100, 2011.
 155. Warncke J, David S, Kumpers P, Opherk JP, Haller H, Fliser D. A hibernating kidney ‐ ischemic preconditioning in a renal transplant recipient with a proximal stenosis of the iliac artery. Clin Nephrol 70: 168‐171, 2008.
 156. Warner L, Glockner JF, Woollard J, Textor SC, Romero JC, Lerman LO. Determinations of renal cortical and medullary oxygenation using blood oxygen level‐dependent magnetic resonance imaging and selective diuretics. Invest Radiol 46: 41‐47, 2011.
 157. Watorek E, Paprocka M, Dus D, Kopec W, Klinger M. Endostatin and vascular endothelial growth factor: potential regulators of endothelial progenitor cell number in chronic kidney disease. Pol Arch Med Wewn 121: 296‐301, 2011.
 158. Weis M, Heeschen C, Glassford AJ, Cooke JP. Statins have biphasic effects on angiogenesis. Circulation 105: 739‐745, 2002.
 159. Whayne TF, Jr. Coronary atherosclerosis, low‐density lipoproteins and markers of thrombosis, inflammation and endothelial dysfunction. Int J Angiol 16: 12‐16, 2007.
 160. Yang F, Chung AC, Huang XR, Lan HY. Angiotensin II induces connective tissue growth factor and collagen I expression via transforming growth factor‐beta‐dependent and ‐independent Smad pathways: The role of Smad3. Hypertension 54: 877‐884, 2009.
 161. Zhu M, Bi X, Jia Q, Shangguan S. The possible mechanism for impaired angiogenesis after transient focal ischemia in type 2 diabetic GK rats: different expressions of angiostatin and vascular endothelial growth factor. Biomed Pharmacother 64: 208‐213, 2010.
 162. Zhu XY, Chade AR, Rodriguez‐Porcel M, Bentley MD, Ritman EL, Lerman A, Lerman LO. Cortical microvascular remodeling in the stenotic kidney: Role of increased oxidative stress. Arterioscler Thromb Vasc Biol 24: 1854‐1859, 2004.
 163. Zhu XY, Rodriguez‐Porcel M, Bentley MD, Chade AR, Sica V, Napoli C, Caplice N, Ritman EL, Lerman A, Lerman LO. Antioxidant intervention attenuates myocardial neovascularization in hypercholesterolemia. Circulation 109: 2109‐2115, 2004.
 164. Zoccali C. Endothelial dysfunction in CKD: A new player in town? Nephrol Dial Transplant 23: 783‐785, 2008.
 165. Zoja C, Cattaneo S, Fiordaliso F, Lionetti V, Zambelli V, Salio M, Corna D, Pagani C, Rottoli D, Bisighini C, Remuzzi G, Benigni A. Distinct cardiac and renal effects of ETA receptor antagonist and ACE inhibitor in experimental type 2 diabetes. Am J Physiol Renal Physiol 301: F1114‐F1123, 2011.

Related Articles:

Systemic Hypertension

Contact Editor

Submit a note to the editor about this article by filling in the form below.

* Required Field

Article Title: Renal Vascular Structure and Rarefaction
 

How to Cite

Alejandro R. Chade. Renal Vascular Structure and Rarefaction. Compr Physiol 2013, 3: 817-831. doi: 10.1002/cphy.c120012