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Pathogenesis: Hemodynamic Alterations

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Diabetes and Kidney Disease

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Abstract

Diabetes mellitus is associated with hyperfiltration and hyperreabsorption of the kidney, which is not always obvious, e.g., in patients with impaired overall kidney function due to low nephron endowment or precedent nephron loss due to aging or injury. At the single nephron level, however, hyperfiltration and hyperreabsorption are always present and a central pathomechanism for the progression of chronic to end-stage kidney disease. The renin-angiotensin-aldosterone system (RAAS) is a central mediator of this process largely driven by the upstream role of sodium-glucose-cotransporter-2-driven alterations of the tubular fluid reaching the macula densa. The evolving insights into the complexity of the RAAS and the SGLT2-driven pathomechanisms have completely changed our perception of the role of previously favored pathomechanisms such as glucotoxicity, insulin resistance, inflammation, and fibrosis in the progression of chronic kidney disease in patients with diabetes in general and in diabetic nephropathy in particular. The clinical trial evidence ultimately proved that the altered hemodynamics and persistent activation of the RAAS are the central upstream pathomechanism of diabetes-related kidney hypertrophy and atrophy.

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References

  1. Patel A, MacMahon S, Chalmers J, et al. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008;358:2560–72.

    Article  CAS  PubMed  Google Scholar 

  2. Niewczas MA, Pavkov ME, Skupien J, et al. A signature of circulating inflammatory proteins and development of end-stage renal disease in diabetes. Nat Med. 2019;25:805–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Wada J, Makino H. Innate immunity in diabetes and diabetic nephropathy. Nat Rev Nephrol. 2016;12:13–26.

    Article  CAS  PubMed  Google Scholar 

  4. Karihaloo A. Anti-fibrosis therapy and diabetic nephropathy. Curr Diab Rep. 2012;12:414–22.

    Article  CAS  PubMed  Google Scholar 

  5. Tervaert TWC, Mooyaart AL, Amann K, et al. Pathologic classification of diabetic nephropathy. J Am Soc Nephrol. 2010;21:556–63.

    Article  PubMed  Google Scholar 

  6. Schmid H, Boucherot A, Yasuda Y, et al. Modular activation of nuclear factor-κB transcriptional programs in human diabetic nephropathy. Diabetes. 2006;55:2993–3003.

    Article  CAS  PubMed  Google Scholar 

  7. Suárez-Álvarez B, Liapis H, Anders HJ. Links between coagulation, inflammation, regeneration, and fibrosis in kidney pathology. Lab Investig. 2016;96:378–90.

    Article  PubMed  CAS  Google Scholar 

  8. Voelker J, Berg PH, Sheetz M, et al. Anti-TGF-b1 antibody therapy in patients with diabetic nephropathy. J Am Soc Nephrol. 2017:953–62.

    Google Scholar 

  9. Menne J, Eulberg D, Beyer D, Baumann M, Saudek F, Valkusz Z, Więcek A, Haller H, Group ES. C-C motif-ligand 2 inhibition with emapticap pegol (NOX-E36) in type 2 diabetic patients with albuminuria. Nephrol Dialysis Transplant Off Pub Eur Dialysis Transplant Assoc Eur Renal Assoc. 2017;32:307–15.

    CAS  Google Scholar 

  10. de Zeeuw D, Bekker P, Henkel E, Hasslacher C, Gouni-Berthold I, Mehling H, Potarca A, Tesar V, Heerspink HJL, Schall TJ. The effect of CCR2 inhibitor CCX140-B on residual albuminuria in patients with type 2 diabetes and nephropathy: a randomised trial. Lancet Diabetes Endocrinol. 2015;3:687–96.

    Article  PubMed  CAS  Google Scholar 

  11. Perez-Gomez MV, Sanchez-Niño MD, Sanz AB, Zheng B, Martín-Cleary C, Ruiz-Ortega M, Ortiz A, Fernandez-Fernandez B. Targeting inflammation in diabetic kidney disease: early clinical trials. Expert Opin Investig Drugs. 2016;25:1045–58.

    Article  CAS  PubMed  Google Scholar 

  12. Brenner BM, Cooper ME, de Zeeuw D, Keane WF, Mitch WE, Parving H-H, Remuzzi G, Snapinn SM, Zhang Z, Shahinfar S. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med. 2001;345:861–9.

    Article  CAS  PubMed  Google Scholar 

  13. Weil EJ, Fufaa G, Jones LI, et al. Effect of losartan on prevention and progression of early diabetic nephropathy in American Indians with type 2 diabetes. Diabetes. 2013;62:3224–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Remuzzi G, Benigni A, Remuzzi A. Mechanisms of progression and regression of renal lesions of chronic nephropathies and diabetes. J Clin Investig. 2006;116:288–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Romagnani P, Remuzzi G, Glassock R, Levin A, Jager KJ, Tonelli M, Massy Z, Wanner C, Anders HJ. Chronic kidney disease. Nat Rev Dis Primers. 2017; https://doi.org/10.1038/nrdp.2017.88.

  16. Anders HJ, Huber TB, Isermann B, Schiffer M. CKD in diabetes: diabetic kidney disease versus nondiabetic kidney disease. Nat Rev Nephrol. 2018;14:361–77.

    Article  CAS  PubMed  Google Scholar 

  17. Denic A, Lieske JC, Chakkera HA, Poggio ED, Alexander MP, Singh P, Kremers WK, Lerman LO, Rule AD. The substantial loss of nephrons in healthy human kidneys with aging. J Am Soc Nephrol. 2017;28:313–20.

    Article  PubMed  Google Scholar 

  18. Denic A, Mathew J, Lerman LO, Lieske JC, Larson JJ, Alexander MP, Poggio E, Glassock RJ, Rule AD. Single-nephron glomerular filtration rate in healthy adults. N Engl J Med. 2017;376:2349–57.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Hommos MS, Glassock RJ, Rule AD. Structural and functional changes in human kidneys with healthy aging. J Am Soc Nephrol. 2017;28:2838–44.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Tonneijck L, Muskiet MHA, Smits MM, Van Bommel EJ, Heerspink HJL, Van Raalte DH, Joles JA. Glomerular hyperfiltration in diabetes: mechanisms, clinical significance, and treatment. J Am Soc Nephrol. 2017;28:1023–39.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Roca-Ho H, Riera M, Palau V, Pascual J, Soler MJ. Characterization of ACE and ACE2 expression within different organs of the NOD mouse. Int J Mol Sci. 2017; https://doi.org/10.3390/ijms18030563.

  22. Márquez E, Riera M, Pascual J, Soler MJ. Renin-angiotensin system within the diabetic podocyte. Am J Physiol Ren Physiol. 2015; https://doi.org/10.1152/ajprenal.00531.2013.

  23. Crackower MA, Sarao R, Oudit GY, et al. Angiotensin-converting enzyme 2 is an essential regulator of heart function. Nature. 2002;417:822–8.

    Article  CAS  PubMed  Google Scholar 

  24. Soler MJ, Wysocki J, Batlle D. ACE2 alterations in kidney disease. Nephrol Dialysis Transplant. 2013; https://doi.org/10.1093/ndt/gft320.

  25. Clotet S, Riera M, Pascual J, Soler MJ. RAS and sex differences in diabetic nephropathy. Am J Physiol Ren Physiol. 2016; https://doi.org/10.1152/ajprenal.00292.2015.

  26. Soler MJ, Lloveras J, Batlle D. Angiotensin converting enzyme 2 and its emerging role in the regulation of the renin angiotensin system. Med Clin. 2008; https://doi.org/10.1157/13124619.

  27. Matsusaka T, Niimura F, Shimizu A, Pastan I, Saito A, Kobori H, Nishiyama A, Ichikawa I. Liver angiotensinogen is the primary source of renal angiotensin II. J Am Soc Nephrol. 2012;23:1181–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Dickson ME, Zimmerman MB, Rahmouni K, Sigmund CD. The −20 and −217 promoter variants dominate differential angiotensinogen haplotype regulation in angiotensinogen-expressing cells. In: Hypertension. Hypertension; 2007. p. 631–9.

    Google Scholar 

  29. Yamaleyeva LM, Gilliam-Davis S, Almeida I, Bridget Brosnihan K, Lindsey SH, Chappell MC. Differential regulation of circulating and renal ACE2 and ACE in hypertensive mRen2.Lewis rats with early-onset diabetes. Am J Physiol Ren Physiol. 2012; https://doi.org/10.1152/ajprenal.00656.2011.

  30. Kobori H, Katsurada A, Miyata K, Ohashi N, Satou R, Saito T, Hagiwara Y, Miyashita K, Navar LG. Determination of plasma and urinary angiotensinogen levels in rodents by newly developed ELISA. Am J Physiol Ren Physiol. 2008;294:F1257.

    Article  CAS  Google Scholar 

  31. Yamamoto T, Nakagawa T, Suzuki H, Ohashi N, Fukasawa H, Fujigaki Y, Kato A, Nakamura Y, Suzuki F, Hishida A. Urinary angiotensinogen as a marker of intrarenal angiotensin II activity associated with deterioration of renal function in patients with chronic kidney disease. J Am Soc Nephrol. 2007;18:1558–65.

    Article  CAS  PubMed  Google Scholar 

  32. Kamiyama M, Urushihara M, Morikawa T, Konishi Y, Imanishi M, Nishiyama A, Kobori H. Oxidative stress/angiotensinogen/renin-angiotensin system axis in patients with diabetic nephropathy. Int J Mol Sci. 2013;14:23045–62.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Ba Aqeel S, Ye M, Wysocki J, et al. Urinary angiotensinogen antedates the development of stage 3 CKD in patients with type 1 diabetes mellitus. Physiol Rep. 2019; https://doi.org/10.14814/phy2.14242.

  34. Terami T, Wada J, Inoue K, Nakatsuka A, Ogawa D, Teshigawara S, Murakami K, Katayama A, Eguchi J, Makino H. Urinary angiotensinogen is a marker for tubular injuries in patients with type 2 diabetes. Int J Nephrol Renov Dis. 2013;6:233–40.

    Google Scholar 

  35. Siragy HM. Angiotensin II compartmentalization within the kidney: effects of salt diet and blood pressure alterations. Curr Opin Nephrol Hypertens. 2006;15:50–3.

    Article  CAS  PubMed  Google Scholar 

  36. Chen D, Coffman TM. AT1 angiotensin receptors—vascular and renal epithelial pathways for blood pressure regulation. Curr Opin Pharmacol. 2015;21:122–6.

    Article  CAS  PubMed  Google Scholar 

  37. Jennings BL, Anderson LJ, Estes AM, Fang XR, Song CY, Campbell WB, Malik KU. Involvement of cytochrome P-450 1B1 in renal dysfunction, injury, and inflammation associated with angiotensin II-induced hypertension in rats. Am J Physiol Ren Physiol. 2012;302:F408.

    Article  CAS  Google Scholar 

  38. Wolf G. Role of reactive oxygen species in angiotensin II-mediated renal growth, differentiation, and apoptosis. Antioxid Redox Signal. 2005;7:1337–45.

    Article  CAS  PubMed  Google Scholar 

  39. Clotet-Freixas S, Soler MJ, Palau V, Anguiano L, Gimeno J, Konvalinka A, Pascual J, Riera M. Sex dimorphism in ANGII-mediated crosstalk between ACE2 and ACE in diabetic nephropathy. Lab Investig. 2018; https://doi.org/10.1038/s41374-018-0084-x.

  40. Ola MS, Alhomida AS, Ferrario CM, Ahmad S. Role of tissue renin-angiotensin system and the Chymase/angiotensin-( 1-12) Axis in the pathogenesis of diabetic retinopathy. Curr Med Chem. 2017; https://doi.org/10.2174/0929867324666170407141955.

  41. Park S, Bivona BJ, Kobori H, Seth DM, Chappell MC, Lazartigues E, Harrison-Bernard LM. Major role for ACE-independent intrarenal ANG II formation in type II diabetes. Am J Physiol Ren Physiol. 2010;298:F37.

    Article  CAS  Google Scholar 

  42. Zhuo JL, Li XC. Novel roles of intrine angiotensin II and signalling mechanisms in kidney cells. JRAAS - J Renin-Angiotensin-Aldosterone Syst. 2007;8:23–33.

    Article  CAS  PubMed  Google Scholar 

  43. Hakam AC, Siddiqui AH, Hussain T. Renal angiotensin II AT 2 receptors promote natriuresis in streptozotocin-induced diabetic rats. Am J Physiol Renal Physiol. 2006;290:F503–8.

    Article  CAS  PubMed  Google Scholar 

  44. Razga Z, Kovacs G, Bódi N, Talapka P, Nyengaard JR. Heterogeneous downregulation of angiotensin II AT1-a and AT1-B receptors in arterioles in STZ-induced diabetic rat kidneys. Biomed Res Int. 2014; https://doi.org/10.1155/2014/947506.

  45. Sabuhi R, Ali Q, Asghar M, Al-Zamily NRH, Hussain T. Role of the angiotensin II AT2 receptor in inflammation and oxidative stress: opposing effects in lean and obese Zucker rats. Am J Physiol Ren Physiol. 2011; https://doi.org/10.1152/ajprenal.00616.2010.

  46. Castoldi G, Di Gioia CRT, Bombardi C, Maestroni S, Carletti R, Steckelings UM, Dahlöf B, Unger T, Zerbini G, Stella A. Prevention of diabetic nephropathy by compound 21, selective agonist of angiotensin type 2 receptors, in Zucker diabetic fatty rats. Am J Physiol Renal Physiol. 2014;307:1123–31.

    Article  CAS  Google Scholar 

  47. Castoldi G, di Gioia CRT, Bombardi C, Maestroni S, Carletti R, Steckelings UM, Dahlöf B, Unger T, Zerbini G, Stella A. Prevention of diabetic nephropathy by compound 21, selective agonist of angiotensin type 2 receptors, in Zucker diabetic fatty rats. Am J Physiol Ren Physiol. 2014;307:F1123–31.

    Article  CAS  Google Scholar 

  48. Donoghue M, Hsieh F, Baronas E, et al. A novel angiotensin-converting enzyme-related carboxypeptidase (ACE2) converts angiotensin I to angiotensin 1-9. Circ Res. 2000;87:E1–9.

    Article  CAS  PubMed  Google Scholar 

  49. Soler MJ, Wysocki J, Batlle D. Angiotensin-converting enzyme 2 and the kidney. Exp Physiol. 2008; https://doi.org/10.1113/expphysiol.2007.041350.

  50. Wysocki J, Ye M, Soler MJ, Gurley SB, Xiao HD, Bernstein KE, Coffman TM, Chen S, Batlle D. ACE and ACE2 activity in diabetic mice. Diabetes. 2006; https://doi.org/10.2337/db06-0033.

  51. Ye M, Wysocki J, William J, Soler MJ, Cokic I, Batlle D. Glomerular localization and expression of angiotensin-converting enzyme 2 and angiotensin-converting enzyme: implications for albuminuria in diabetes. J Am Soc Nephrol. 2006; https://doi.org/10.1681/ASN.2006050423.

  52. Soler MJ, Ye M, Wysocki J, William J, Lloveras J, Batlle D. Localization of ACE2 in the renal vasculature: amplification by angiotensin II type 1 receptor blockade using telmisartan. Am J Physiol Ren Physiol. 2009; https://doi.org/10.1152/ajprenal.90488.2008.

  53. Riera M, Márquez E, Clotet S, Gimeno J, Roca-Ho H, Lloreta J, Juanpere N, Batlle D, Pascual J, Soler MJ. Effect of insulin on ACE2 activity and kidney function in the non-obese diabetic mouse. PLoS One. 2014; https://doi.org/10.1371/journal.pone.0084683.

  54. Tikellis C, Johnston CI, Forbes JM, Burns WC, Burrell LM, Risvanis J, Cooper ME. Characterization of renal angiotensin - converting enzyme 2 in diabetic nephropathy. Hypertension. 2003;41:392–7.

    Article  CAS  PubMed  Google Scholar 

  55. Valdivielso JM, Jacobs-Cachá C, Soler MJ. Sex hormones and their influence on chronic kidney disease. Curr Opin Nephrol Hypertens. 2019;28:1–9.

    Article  CAS  PubMed  Google Scholar 

  56. Soler MJ, Wysocki J, Ye M, Lloveras J, Kanwar Y, Batlle D. ACE2 inhibition worsens glomerular injury in association with increased ACE expression in streptozotocin-induced diabetic mice. Kidney Int. 2007; https://doi.org/10.1038/sj.ki.5002373.

  57. Roca-Ho H, Palau V, Gimeno J, Pascual J, Soler MJ, Riera M. Angiotensin-converting enzyme 2 influences pancreatic and renal function in diabetic mice. Lab Investig. 2020; https://doi.org/10.1038/s41374-020-0440-5.

  58. Soro-Paavonen A, Gordin D, Forsblom C, Rosengard-Barlund M, Waden J, Thorn L, Sandholm N, Thomas MC, Groop PH. Circulating ACE2 activity is increased in patients with type 1 diabetes and vascular complications. J Hypertens. 2012;30:375–83.

    Article  CAS  PubMed  Google Scholar 

  59. Anguiano L, Riera M, Pascual J, et al. Circulating angiotensin-converting enzyme 2 activity in patients with chronic kidney disease without previous history of cardiovascular disease. Nephrol Dialysis Transplant. 2015; https://doi.org/10.1093/ndt/gfv025.

  60. Sparks MA, South A, Welling P, et al. Sound science before quick judgement regarding RAS blockade in COVID-19. Clin J Am Soc Nephrol. 2020;15:714–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Wysocki J, Lores E, Ye M, Soler MJ, Batlle D. Kidney and lung ACE2 expression after an ACE inhibitor or an Ang II receptor blocker: implications for COVID-19. J Am Soc Nephrol. 2020;ASN.2020050667

    Google Scholar 

  62. Igase M, Strawn WB, Gallagher PE, Geary RL, Ferrario CM. Angiotensin II at1 receptors regulate ACE2 and angiotensin-(1-7) expression in the aorta of spontaneously hypertensive rats. Am J Physiol Heart Circ Physiol. 2005; https://doi.org/10.1152/ajpheart.00068.2005.

  63. Velez JCQ, Bland AM, Arthur JM, Raymond JR, Janech MG. Characterization of renin-angiotensin system enzyme activities in cultured mouse podocytes. Am J Physiol Ren Physiol. 2007;293:398–407.

    Article  CAS  Google Scholar 

  64. Trask AJ, Ferrario CM. Angiotensin-(1-7): pharmacology and new perspectives in cardiovascular treatments. Cardiovasc Drug Rev. 2007;25:162–74.

    Article  CAS  PubMed  Google Scholar 

  65. Bertoncello N, Moreira RP, Arita DY, et al. Diabetic nephropathy induced by increased ace gene dosage is associated with high renal levels of angiotensin (1-7) and bradykinin. J Diabetes Res. 2015; https://doi.org/10.1155/2015/674047.

  66. Benter IF, Yousif MHM, Dhaunsi GS, Kaur J, Chappell MC, Diz DI. Angiotensin-(1-7) prevents activation of NADPH oxidase and renal vascular dysfunction in diabetic hypertensive rats. Am J Nephrol. 2007;28:25–33.

    Article  PubMed  CAS  Google Scholar 

  67. Persson P, Fasching A, Palm F. Acute intrarenal angiotensin (1-7) infusion decreases diabetes-induced glomerular hyperfiltration but increases kidney oxygen consumption in the rat. Acta Physiol. 2019; https://doi.org/10.1111/apha.13254.

  68. Xu P, Sriramula S, Lazartigues E. ACE2/ANG-(1-7)/mas pathway in the brain: the axis of good. Am J Physiol Regul Integr Comp Physiol. 2011;300:804–17.

    Article  CAS  Google Scholar 

  69. Catanzaro DF. Molecular biology of renin and regulation of its gene. In: Textbook of Nephro-endocrinology. Elsevier; 2018. p. 389–400.

    Chapter  Google Scholar 

  70. Shinagawa T, Doi Y, Hashiba K, Yano K, Nakayama K, Uchiyama Y, Kominami E, Hsueh WA, Murakami K. Role of Cathepsin B as Prorenin processing enzyme in human kidney. Hypertension Res Clin Exp. 1995;18:131–6.

    Article  CAS  Google Scholar 

  71. Neves FAR, Duncan KG, Baxter JD. Cathepsin B is a prorenin processing enzyme. In: Hypertension. Hypertension; 1996. p. 514–7.

    Google Scholar 

  72. Wang PH, Do YS, Macaulay L, Shinagawa T, Anderson PW, Baxter JD, Hsueh WA. Identification of renal cathepsin B as a human prorenin-processing enzyme. J Biol Chem. 1991;266:12633–8.

    Article  CAS  PubMed  Google Scholar 

  73. Hsueh WA, Baxter JD (1991) Human Prorenin.

    Google Scholar 

  74. Nguyen G, Delarue F, Burcklé C, Bouzhir L, Giller T, Sraer J-D. Pivotal role of the renin/prorenin receptor in angiotensin II production and cellular responses to renin. J Clin Investig. 2002;109:1417–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Ramkumar N, Kohan DE. The (pro)renin receptor: an emerging player in hypertension and metabolic syndrome. Kidney Int. 2019;95:1041–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Cousin C, Bracquart D, Contrepas A, Corvol P, Muller L, Nguyen G. Soluble form of the (pro)renin receptor generated by intracellular cleavage by furin is secreted in plasma. Hypertension. 2009;53:1077–82.

    Article  CAS  PubMed  Google Scholar 

  77. Batenburg WW, Krop M, Garrelds IM, De Vries R, De Bruin RJA, Burcklé CA, Müller DN, Bader M, Nguyen G, Danser AHJ. Prorenin is the endogenous agonist of the (pro)renin receptor. Binding kinetics of renin and prorenin in rat vascular smooth muscle cells overexpressing the human (pro)renin receptor. J Hypertens. 2007;25:2441–53.

    Article  CAS  PubMed  Google Scholar 

  78. Nguyen G, Muller DN. The biology of the (pro)renin receptor. J Am Soc Nephrol. 2010;21:18–23.

    Article  CAS  PubMed  Google Scholar 

  79. Tang J, Wysocki J, Ye M, et al. Urinary renin in patients and mice with diabetic kidney disease. Hypertension. 2019;74:83–94.

    Article  CAS  PubMed  Google Scholar 

  80. Van Den Heuvel M, Batenburg WW, Jainandunsing S, Garrelds IM, Van Gool JMG, Feelders RA, Van Den Meiracker AH, Danser AHJ. Urinary renin, but not angiotensinogen or aldosterone, reflects the renal renin-angiotensin-aldosterone system activity and the efficacy of renin-angiotensin-aldosterone system blockade in the kidney. J Hypertens. 2011;29:2147–55.

    Article  PubMed  CAS  Google Scholar 

  81. Riera M, Anguiano L, Clotet S, Roca-Ho H, Rebull M, Pascual J, Soler MJ. Paricalcitol modulates ACE2 shedding and renal ADAM17 in NOD mice beyond proteinuria. Am J Physiol Renal Physiol. 2016;310:F534–46.

    Article  CAS  PubMed  Google Scholar 

  82. Deb DK, Sun T, Wong KE, Zhang Z, Ning G, Zhang Y, Kong J, Shi H, Chang A, Li YC. Combined vitamin D analog and AT1 receptor antagonist synergistically block the development of kidney disease in a model of type 2 diabetes. Kidney Int. 2010;77:1000–9.

    Article  CAS  PubMed  Google Scholar 

  83. Liu Y, Li H, Liu J, et al. Variations in MicroRNA-25 expression influence the severity of diabetic kidney disease. J Am Soc Nephrol. 2017;28:3627–38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Li Z, Zhou L, Wang Y, Miao J, Hong X, Hou FF, Liu Y. (pro)renin receptor is an amplifier of Wnt/β-catenin signaling in kidney injury and fibrosis. J Am Soc Nephrol. 2017;28:2393–408.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Tojo A, Kinugasa S, Fujita T, Wilcox CS. A local renal renin–angiotensin system activation via renal uptake of prorenin and angiotensinogen in diabetic rats. Diabetes Metabolic Syndrome Obesity Targets Therapy. 2016;9:1–10.

    Article  CAS  Google Scholar 

  86. Akhtar S, Siragy HM. Pro-renin receptor suppresses mitochondrial biogenesis and function via AMPK/SIRT-1/ PGC-1α pathway in diabetic kidney. PLoS One. 2019;14:e0225728.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Huang Y, Wongamorntham S, Kasting J, McQuillan D, Owens RT, Yu L, Noble NA, Border W. Renin increases mesangial cell transforming growth factor-β1 and matrix proteins through receptor-mediated, angiotensin II-independent mechanisms. Kidney Int. 2006;69:105–13.

    Article  CAS  PubMed  Google Scholar 

  88. Narumi K, Sato E, Hirose T, Yamamoto T, Nakamichi T, Miyazaki M, Sato H, Ito S. (pro)renin receptor is involved in mesangial fibrosis and matrix expansion. Sci Rep. 2018; https://doi.org/10.1038/s41598-017-18314-w.

  89. Takahashi H, Ichihara A, Kaneshiro Y, Inomata K, Sakoda M, Takemitsu T, Nishiyama A, Itoh H. Regression of nephropathy developed in diabetes by (pro)renin receptor blockade. J Am Soc Nephrol. 2007;18:2054–61.

    Article  CAS  PubMed  Google Scholar 

  90. Zhang L, An XF, Ruan X, Huang DD, Zhou L, Xue H, Lu LM, He M. Inhibition of (pro)renin receptor contributes to renoprotective effects of angiotensin ii type 1 receptor blockade in diabetic nephropathy. Front Physiol. 2017; https://doi.org/10.3389/fphys.2017.00758.

  91. Price DA, Porter LE, Gordon M, Fisher NDL, De’oliveira JMF, Laffel LMB, Passan DR, Williams GH, Hollenberg NK. The paradox of the low-renin state in diabetic nephropathy. J Am Soc Nephrol. 1999;10:2382–91.

    Article  CAS  PubMed  Google Scholar 

  92. King JA, Fray JCS. Hydrogen and potassium regulation of (pro)renin processing and secretion. Am J Physiol Renal Fluid Electrolyte Physiology. 1994; https://doi.org/10.1152/ajprenal.1994.267.1.f1.

  93. Paulsen EP, Seip RL, Ayers CR, Croft BY, Kaiser DL. Plasma renin activity and albumin excretion in teenage type I diabetic subjects a prospective study. Hypertension. 1989;13:781–8.

    Article  CAS  PubMed  Google Scholar 

  94. Hollenberg NK, Stevanovic R, Agarwal A, Lansang MC, Price DA, Laffel LMB, Williams GH, Fisher NDL. Plasma aldosterone concentration in the patient with diabetes mellitus: rapid communication. Kidney Int. 2004;65:1435–9.

    Article  CAS  PubMed  Google Scholar 

  95. Helal I, Fick-Brosnahan GM, Reed-Gitomer B, Schrier RW. Glomerular hyperfiltration: definitions, mechanisms and clinical implications. Nat Rev Nephrol. 2012;8:293–300.

    Article  CAS  PubMed  Google Scholar 

  96. García-Carro C, Vergara A, Agraz I, Jacobs-Cachá C, Espinel E, Seron D, Soler MJ. The new era for Reno-cardiovascular treatment in type 2 diabetes. J Clin Med. 2019;8:864.

    Article  PubMed Central  CAS  Google Scholar 

  97. Chen AX, Jerums G, Baqar S, Lambert E, Somarajah G, Thomas G, O’Callaghan C, MacIsaac RJ, Ekinci EI. Short-term dietary salt supplementation blunts telmisartan induced increases in plasma renin activity in hypertensive patients with type 2 diabetes mellitus. Clin Sci. 2015;129:415–22.

    Article  CAS  Google Scholar 

  98. Isshiki M, Sakuma I, Hayashino Y, et al. Effects of dapagliflozin on renin-angiotensin-aldosterone system under renin-angiotensin system inhibitor administration. Endocr J. 2020; https://doi.org/10.1507/endocrj.EJ20-0222.

  99. Nguyen G, Blanchard A, Curis E, et al. Plasma soluble (pro)renin receptor is independent of plasma renin, prorenin, and aldosterone concentrations but is affected by ethnicity. Hypertension. 2014;63:297–302.

    Article  CAS  PubMed  Google Scholar 

  100. Franken AAM, Derkx FHM, Man In’t Veld AJ, Hop WCJ, Van Rens GH, Peperkamp E, De Jong PTVM, Schalekamp MADH. High plasma prorenin in diabetes mellitus and its correlation with some complications. J Clin Endocrinol Metab. 1990;71:1008–15.

    Article  CAS  PubMed  Google Scholar 

  101. Deinum J, Tarnow L, Van Gool JM, De Bruin RA, Derkx FHM, Schalekamp MADH, Parving HH. Plasma renin and prorenin and renin gene variation in patients with insulin-dependent diabetes mellitus and nephropathy. Nephrol Dialysis Transplant. 1999;14:1904–11.

    Article  CAS  Google Scholar 

  102. Yokota H, Mori F, Kai K, Nagaoka T, Izumi N, Takahashi A, Hikichi T, Yoshida A, Suzuki F, Ishida Y. Serum prorenin levels and diabetic retinopathy in type 2 diabetes: new method to measure serum level of prorenin using antibody activating direct kinetic assay. Br J Ophthalmol. 2005;89:871–3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Hamada K, Taniguchi Y, Shimamura Y, et al. Serum level of soluble (pro)renin receptor is modulated in chronic kidney disease. Clin Exp Nephrol. 2013;17:848–56.

    Article  CAS  PubMed  Google Scholar 

  104. Kopp UC (2011) Neural control of renin secretion rate.

    Google Scholar 

  105. Chang C-H, Hu Y-H, Huang K-H, et al. Higher screening aldosterone to renin ratio in primary Aldosteronism patients with diabetes mellitus. J Clin Med. 2018;7:360.

    Article  CAS  PubMed Central  Google Scholar 

  106. Umpierrez GE, Cantey P, Smiley D, Palacio A, Temponi D, Luster K, Chapman A. Primary Aldosteronism in diabetic subjects with resistant hypertension. Diabetes Care. 2007;30:1699–703.

    Article  CAS  PubMed  Google Scholar 

  107. Scott JH, Dunn RJ. Physiology, aldosterone. StatPearls Publishing; 2019.

    Google Scholar 

  108. Azushima K, Morisawa N, Tamura K, Nishiyama A. Recent research advances in renin-angiotensin-aldosterone system receptors. Curr Hypertens Rep. 2020;22:22.

    Article  PubMed  Google Scholar 

  109. Mihailidou AS, Tzakos AG, Ashton AW. Non-genomic effects of aldosterone. In: Vitamins and hormones. Academic Press Inc; 2019. p. 133–49.

    Google Scholar 

  110. Barrera-Chimal J, Estrela GR, Lechner SM, Giraud S, El Moghrabi S, Kaaki S, Kolkhof P, Hauet T, Jaisser F. The myeloid mineralocorticoid receptor controls inflammatory and fibrotic responses after renal injury via macrophage interleukin-4 receptor signaling. Kidney Int. 2018;93:1344–55.

    Article  CAS  PubMed  Google Scholar 

  111. Barrera-Chimal J, Pérez-Villalva R, Ortega JA, Sánchez A, Rodríguez-Romo R, Durand M, Jaisser F, Bobadilla NA. Mild ischemic injury leads to long-term alterations in the kidney: amelioration by spironolactone administration. Int J Biol Sci. 2015;11:892–900.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Mejía-Vilet JM, Ramírez V, Cruz C, Uribe N, Gamba G, Bobadilla NA. Renal ischemia-reperfusion injury is prevented by the mineralocorticoid receptor blocker spironolactone. Am J Physiol Ren Physiol. 2007; https://doi.org/10.1152/ajprenal.00077.2007.

  113. Asai M, Monkawa T, Marumo T, Fukuda S, Tsuji M, Yoshino J, Kawachi H, Shimizu F, Hayashi M, Saruta T. Spironolactone in combination with cilazapril ameliorates proteinuria and renal interstitial fibrosis in rats with anti-Thy-1 irreversible nephritis. Hypertens Res. 2004;27:971–8.

    Article  CAS  PubMed  Google Scholar 

  114. Feria I, Pichardo I, Juárez P, Ramírez V, González MA, Uribe N, García-Torres R, López-Casillas F, Gamba G, Bobadilla NA. Therapeutic benefit of spironolactone in experimental chronic cyclosporine a nephrotoxicity. Kidney Int. 2003;63:43–52.

    Article  CAS  PubMed  Google Scholar 

  115. Baker ME, Funder JW, Kattoula SR. Evolution of hormone selectivity in glucocorticoid and mineralocorticoid receptors. J Steroid Biochem Mol Biol. 2013;137:57–70.

    Article  CAS  PubMed  Google Scholar 

  116. Han KH, Kang YS, Han SY, Jee YH, Lee MH, Han JY, Kim HK, Kim YS, Cha DR. Spironolactone ameliorates renal injury and connective tissue growth factor expression in type II diabetic rats. Kidney Int. 2006;70:111–20.

    Article  CAS  PubMed  Google Scholar 

  117. Taira M, Toba H, Murakami M, Iga I, Serizawa R, Murata S, Kobara M, Nakata T. Spironolactone exhibits direct renoprotective effects and inhibits renal renin-angiotensin-aldosterone system in diabetic rats. Eur J Pharmacol. 2008;589:264–71.

    Article  CAS  PubMed  Google Scholar 

  118. Guo C, Martinez-Vasquez D, Mendez GP, et al. Mineralocorticoid receptor antagonist reduces renal injury in rodent models of types 1 and 2 diabetes mellitus. Endocrinology. 2006;147:5363–73.

    Article  CAS  PubMed  Google Scholar 

  119. Fujisawa G, Okada K, Muto S, Fujita N, Itabashi N, Kusano E, Ishibashi S. Spironolactone prevents early renal injury in streptozotocin-induced diabetic rats. Kidney Int. 2004;66:1493–502.

    Article  CAS  PubMed  Google Scholar 

  120. Molina-Jijón E, Rodríguez-Muñoz R, González-Ramírez R, Namorado-Tónix C, Pedraza-Chaverri J, Reyes JL. Aldosterone signaling regulates the over-expression of. PLoS One. 2017; https://doi.org/10.1371/journal.pone.0177362.

  121. Dong D, Ting FT, Shi JY, Yu YJ, Wu S, Zhang L. Spironolactone alleviates diabetic nephropathy through promoting autophagy in podocytes. Int Urol Nephrol. 2019;51:755–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Kosugi T, Heinig M, Nakayama T, Matsuo S, Nakagawa T. eNOS knockout mice with advanced diabetic nephropathy have less benefit from renin-angiotensin blockade than from aldosterone receptor antagonists. Am J Pathol. 2010;176:619–29.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Barrera-Chimal J, Girerd S, Jaisser F. Mineralocorticoid receptor antagonists and kidney diseases: pathophysiological basis. Kidney Int. 2019;96:302–19.

    Article  CAS  PubMed  Google Scholar 

  124. González-Mariscal L, Tapia R, Chamorro D. Crosstalk of tight junction components with signaling pathways. Biochim Biophys Acta Biomembr. 2008;1778:729–56.

    Article  CAS  Google Scholar 

  125. Zhou G, Johansson U, Peng X-R, Bamberg K, Huang Y. An additive effect of eplerenone to ACE inhibitor on slowing the progression of diabetic nephropathy in the db/db mice. Am J Transl Res. 2016;8:1339–54.

    CAS  PubMed  PubMed Central  Google Scholar 

  126. Kang YS, Ko GJ, Lee MH, Song HK, Han SY, Han KH, Kim HK, Han JY, Cha DR. Effect of eplerenone, enalapril and their combination treatment on diabetic nephropathy in type II diabetic rats. Nephrol Dialysis Transplant. 2009;24:73–84.

    Article  CAS  Google Scholar 

  127. Mavrakanas TA, Cheva A, Kallaras K, Karkavelas G, Mironidou-Tzouveleki M. Effect of ramipril alone compared to ramipril with eplerenone on diabetic nephropathy in streptozocin-induced diabetic rats. Pharmacology. 2010;86:85–91.

    Article  CAS  PubMed  Google Scholar 

  128. Bakris GL, Agarwal R, Chan JC, et al. Effect of finerenone on albuminuria in patients with diabetic nephropathy a randomized clinical trial. JAMA - J Am Med Assoc. 2015;314:884–94.

    Article  CAS  Google Scholar 

  129. Epstein M, Williams GH, Weinberger M, Lewin A, Krause S, Mukherjee R, Patni R, Beckerman B. Selective aldosterone blockade with eplerenone reduces albuminuria in patients with type 2 diabetes. Clin J Am Soc Nephrol CJASN. 2006;1:940–51.

    Article  CAS  PubMed  Google Scholar 

  130. Moranne O, Bakris G, Fafin C, Favre G, Pradier C, Esnault VLM. Determinants and changes associated with aldosterone breakthrough after angiotensin II receptor blockade in patients with type 2 diabetes with overt nephropathy. Clin J Am Soc Nephrol. 2013;8:1694–701.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Pavo N, Arfsten H, Cho A, et al. The circulating form of neprilysin is not a general biomarker for overall survival in treatment-naïve cancer patients. Sci Rep. 2019;9:1–8.

    Article  CAS  Google Scholar 

  132. Gee NS, Bowes MA, Buck P, Kenny AJ. An immunoradiometric assay for endopeptidase-24.11 shows it to be a widely distributed enzyme in pig tissues. Biochem J. 1985;228:119–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Spillantini MG, Sicuteri F, Salmon S, Malfroy B. Characterization of endopeptidase 3.4.24.11 (“enkephalinase”) activity in human plasma and cerebrospinal fluid. Biochem Pharmacol. 1990;39:1353–6.

    Article  CAS  PubMed  Google Scholar 

  134. Meems L, Chen Y, Burnett JC. The cardiac natriuretic peptide system. In: Textbook of Nephro-endocrinology. Elsevier; 2018. p. 163–71.

    Chapter  Google Scholar 

  135. Wysocki J, Ortiz-Melo DI, Mattocks NK, et al. ACE2 deficiency increases NADPH-mediated oxidative stress in the kidney. Physiol Rep. 2014; https://doi.org/10.1002/phy2.264.

  136. Domenig O, Manzel A, Grobe N, et al. Neprilysin is a mediator of alternative renin-angiotensin-system activation in the murine and human kidney. Sci Rep. 2016;6:1–11.

    Article  CAS  Google Scholar 

  137. Alawi LF, Emberesh SE, Owuor BA, Chodavarapu H, Fadnavis R, El-Amouri SS, Elased KM. Effect of hyperglycemia and rosiglitazone on renal and urinary neprilysin in db/db diabetic mice. Physiol Rep. 2020; https://doi.org/10.14814/phy2.14364.

  138. Gutta S, Grobe N, Kumbaji M, Osman H, Saklayen M, Li G, Elased KM. Increased urinary angiotensin converting enzyme 2 and neprilysin in patients with type 2 diabetes. Am J Physiol Ren Physiol. 2018;315:F263–74.

    Article  CAS  Google Scholar 

  139. Guillén-Gómez E, Bardají-de-Quixano B, Ferrer S, et al. Urinary proteome analysis identified Neprilysin and VCAM as proteins involved in diabetic nephropathy. J Diabetes Res. 2018;2018:6165303.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  140. Bayes-Genis A, Prickett TC, Richards AM, Barallat J, Lupón J. Soluble neprilysin retains catalytic activity in heart failure. J Heart Lung Transplant. 2016;35:684–5.

    Article  PubMed  Google Scholar 

  141. Bayés-Genís A, Barallat J, Pascual D, et al. Prognostic value and kinetics of soluble Neprilysin in acute heart failure. Pilot Study JACC Heart Failure. 2015;3:641–4.

    Article  PubMed  Google Scholar 

  142. McMurray JJV, Packer M, Desai AS, et al. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med. 2014;371:993–1004.

    Article  PubMed  CAS  Google Scholar 

  143. Kusaka H, Sueta D, Koibuchi N, Hasegawa Y, Nakagawa T, Lin B, Ogawa H, Kim-Mitsuyama S. LCZ696, angiotensin II receptor-Neprilysin inhibitor, ameliorates high-salt-induced hypertension and cardiovascular injury more than valsartan alone. Am J Hypertens. 2015;28:1409–17.

    Article  CAS  PubMed  Google Scholar 

  144. Rahman A, Sherajee SJ, Rafiq K, Kobara H, Masaki T, Nakano D, Morikawa T, Konishi Y, Imanishi M, Nishiyama A. The angiotensin II receptor-neprilysin inhibitor LCZ696 attenuates the progression of proteinuria in type 2 diabetic rats. J Pharmacol Sci. 2020;142:124–6.

    Article  CAS  PubMed  Google Scholar 

  145. Suematsu Y, Jing W, Nunes A, Kashyap ML, Khazaeli M, Vaziri ND, Moradi H. LCZ696 (Sacubitril/valsartan), an angiotensin-receptor Neprilysin inhibitor, attenuates cardiac hypertrophy, fibrosis, and vasculopathy in a rat model of chronic kidney disease. J Card Fail. 2018;24:266–75.

    Article  CAS  PubMed  Google Scholar 

  146. Habibi J, Aroor AR, Das NA, Manrique-Acevedo CM, Johnson MS, Hayden MR, Nistala R, Wiedmeyer C, Chandrasekar B, Demarco VG. The combination of a neprilysin inhibitor (sacubitril) and angiotensin-II receptor blocker (valsartan) attenuates glomerular and tubular injury in the Zucker obese rat. Cardiovasc Diabetol. 2019; https://doi.org/10.1186/s12933-019-0847-8.

  147. Judge P, Haynes R, Landray MJ, Baigent C. Neprilysin inhibition in chronic kidney disease. Nephrol Dialysis Transplant. 2015;30:738–43.

    Article  CAS  Google Scholar 

  148. Packer M, Claggett B, Lefkowitz MP, McMurray JJV, Rouleau JL, Solomon SD, Zile MR. Effect of neprilysin inhibition on renal function in patients with type 2 diabetes and chronic heart failure who are receiving target doses of inhibitors of the renin-angiotensin system: a secondary analysis of the PARADIGM-HF trial. Lancet Diabetes Endocrinol. 2018;6:547–54.

    Article  CAS  PubMed  Google Scholar 

  149. Störk S. Renal effects of sacubitril/valsartan in patients with diabetes. Lancet Diabetes Endocrinol. 2018;6:519–21.

    Article  PubMed  Google Scholar 

  150. Malek V, Sharma N, Sankrityayan H, Gaikwad AB. Concurrent neprilysin inhibition and renin-angiotensin system modulations prevented diabetic nephropathy. Life Sci. 2019;221:159–67.

    Article  CAS  PubMed  Google Scholar 

  151. Odya CE, Marinkovic DV, Hammon KJ, Stewart TA, Erdös EG. Purification and properties of prolylcarboxypeptidase (angiotensinase C) from human kidney. J Biol Chem. 1978;253:5927–31.

    Article  CAS  PubMed  Google Scholar 

  152. Shariat-Madar Z, Mahdi F, Schmaier AH. Identification and characterization of prolylcarboxypeptidase as an endothelial cell prekallikrein activator. J Biol Chem. 2002;277:17962–9.

    Article  CAS  PubMed  Google Scholar 

  153. Fülöp V, Böcskei Z, Polgár L. Prolyl oligopeptidase: An unusual β-propeller domain regulates proteolysis. Cell. 1998;94:161–70.

    Article  PubMed  Google Scholar 

  154. Welches WR, Bridget Brosnihan K, Ferrario CM. A comparison of the properties and enzymatic activities of three angiotensin processing enzymes: angiotensin converting enzyme, prolyl endopeptidase and neutral endopeptidase 24.11. Life Sci. 1993;52:1461–80.

    Article  CAS  PubMed  Google Scholar 

  155. Serfozo P, Wysocki J, Gulua G, et al. Ang II (angiotensin II) conversion to angiotensin-(1-7) in the circulation is POP (Prolyloligopeptidase)-dependent and ACE2 (angiotensin-converting enzyme 2)-independent. Hypertension (Dallas, Tex : 1979). 2020;75:173–82.

    Article  CAS  Google Scholar 

  156. O’Leary RM, Gallagher SP, O’Connor B. Purification and characterization of a novel membrane-bound form of prolyl endopeptidase from bovine brain. Int J Biochem Cell Biol. 1996;28:441–9.

    Article  PubMed  Google Scholar 

  157. Goossens F, De Meester I, Vanhoof G, Scharpé S. Distribution of prolyl oligopeptidase in human peripheral tissues and body fluids. Eur J Clin Chem Clin Biochem. 1996;34:17–22.

    CAS  PubMed  Google Scholar 

  158. Schulz I, Zeitschel U, Rudolph T, Ruiz-Carrillo D, Rahfeld J-U, Gerhartz B, Bigl V, Demuth H-U, Rossner S. Subcellular localization suggests novel functions for prolyl endopeptidase in protein secretion. J Neurochem. 2005;94:970–9.

    Article  CAS  PubMed  Google Scholar 

  159. Zuo Y, Chun B, Potthoff SA, et al. Thymosin β4 and its degradation product, ac-SDKP, are novel reparative factors in renal fibrosis. Kidney Int. 2013;84:1166–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Barfuss DW, Schafer JA Differences in active and passive glucose transport along the proximal nephron.

    Google Scholar 

  161. Turner RJ, Moran A. Heterogeneity of sodium-dependent D-glucose transport sites along the proximal tubule: evidence from vesicle studies. Am J Physiol Renal Fluid Electrolyte Physiol. 1982; https://doi.org/10.1152/ajprenal.1982.242.4.f406.

  162. Wright EM, LOO DDFL, Hirayama BA (2011) Biology of human sodium glucose transporters. Physiol Rev 91:733–794.

    Google Scholar 

  163. Vallon V, Platt KA, Cunard R, Schroth J, Whaley J, Thomson SC, Koepsell H, Rieg T. SGLT2 mediates glucose reabsorption in the early proximal tubule. J Am Soc Nephrol. 2011;22:104–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Rieg T, Masuda T, Gerasimova M, Mayoux E, Platt K, Powell DR, Thomson SC, Koepsell H, Vallon V. Increase in SGLT1-mediated transport explains renal glucose reabsorption during genetic and pharmacological SGLT2 inhibition in euglycemia. Am J Physiol Ren Physiol. 2014; https://doi.org/10.1152/ajprenal.00518.2013.

  165. Gorboulev V, Schürmann A, Vallon V, et al. Na +-D-glucose cotransporter SGLT1 is pivotal for intestinal glucose absorption and glucose-dependent incretin secretion. Diabetes. 2012;61:187–96.

    Article  CAS  PubMed  Google Scholar 

  166. Vallon V. The mechanisms and therapeutic potential of SGLT2 inhibitors in diabetes mellitus. Annu Rev Med. 2015;66:255–70.

    Article  CAS  PubMed  Google Scholar 

  167. Anders HJ, Davis JM, Thurau K. Nephron protection in diabetic kidney disease. N Engl J Med. 2016;375:2096–8.

    Article  PubMed  Google Scholar 

  168. Cherney DZI, Perkins BA, Soleymanlou N, et al. Renal hemodynamic effect of sodium-glucose cotransporter 2 inhibition in patients with type 1 diabetes mellitus. Circulation. 2014;129:587–97.

    Article  CAS  PubMed  Google Scholar 

  169. Carlström M, Wilcox CS, Arendshorst WJ. Renal autoregulation in health and disease. Physiol Rev. 2015;95:405–511.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  170. Thurau K, Schnermann J. Die Natriumkonzentration an den Macula densa-Zellen als regulierender Faktor für das Glomerulumfiltrat (Mikropunktionsversuche). Klin Wochenschr. 1965;43:410–3.

    Article  CAS  PubMed  Google Scholar 

  171. Thurau KW, Dahlheim H, Grüner A, Mason J, Granger P. Activation of renin in the single juxtaglomerular apparatus by sodium chloride in the tubular fluid at the macula densa. Circ Res. 1972;31(Suppl 2):182–6.

    Google Scholar 

  172. Schnermann J. Concurrent activation of multiple vasoactive signaling pathways in vasoconstriction caused by Tubuloglomerular feedback: a quantitative assessment. Annu Rev Physiol. 2015;77:301–22.

    Article  CAS  PubMed  Google Scholar 

  173. Freitas HS, Anhê GF, Melo KFS, Okamoto MM, Oliveira-Souza M, Bordin S, Machado UF. Na+−glucose transporter-2 messenger ribonucleic acid expression in kidney of diabetic rats correlates with glycemic levels: involvement of hepatocyte nuclear factor-1α expression and activity. Endocrinology. 2008;149:717–24.

    Article  CAS  PubMed  Google Scholar 

  174. Rahmoune H, Thompson PW, Ward JM, Smith CD, Hong G, Brown J. Glucose transporters in human renal proximal tubular cells isolated from the urine of patients with non-insulin-dependent diabetes. Diabetes. 2005;54:3427–34.

    Article  CAS  PubMed  Google Scholar 

  175. Vallon V, Rose M, Gerasimova M, Satriano J, Platt KA, Koepsell H, Cunard R, Sharma K, Thomson SC, Rieg T. Knockout of Na-glucose transporter SGLT2 attenuates hyperglycemia and glomerular hyperfiltration but not kidney growth or injury in diabetes mellitus. Am J Physiol Ren Physiol. 2013; https://doi.org/10.1152/ajprenal.00409.2012.

  176. Thomson SC, Rieg T, Miracle C, Mansoury H, Whaley J, Vallon V, Singh P. Acute and chronic effects of SGLT2 blockade on glomerular and tubular function in the early diabetic rat. Am J Physiol Regul Integr Comp Physiol. 2012;302:R75.

    Article  CAS  PubMed  Google Scholar 

  177. Kidokoro K, Cherney DZI, Bozovic A, Nagasu H, Satoh M, Kanda E, Sasaki T, Kashihara N. Evaluation of glomerular hemodynamic function by Empagliflozin in diabetic mice using in vivo imaging. Circulation. 2019;140:303–15.

    Article  CAS  PubMed  Google Scholar 

  178. Hudkins KL, Wietecha TA, Steegh F, Alpers CE. Beneficial effect on podocyte number in experimental diabetic nephropathy resulting from combined atrasentan and RAAS inhibition therapy. Am J Physiol Ren Physiol. 2020;318:F1295–305.

    Article  CAS  Google Scholar 

  179. Vaněčková I, Hojná S, Vernerová Z, Kadlecová M, Rauchová H, Kompanowska-Jezierska E, Vaňourková Z, Červenka L, Zicha J. Renoprotection provided by additional diuretic treatment in partially Nephrectomized Ren-2 transgenic rats subjected to the combined RAS and ETA blockade. Front Physiol. 2019;10:1145.

    Article  PubMed  PubMed Central  Google Scholar 

  180. Pollock DM, Polakowski JS, Wegner CD, Opgenorth TJ. Beneficial effect of ET(a) receptor blockade in a rat model of radiocontrast-induced nephropathy. Ren Fail. 1997;19:753–61.

    Article  CAS  PubMed  Google Scholar 

  181. Muller ME, Pruijm M, Bonny O, Burnier M, Zanchi A. Effects of the SGLT-2 inhibitor Empagliflozin on renal tissue oxygenation in non-diabetic subjects: a randomized, double-blind, placebo-controlled study protocol. Adv Ther. 2018;35:875–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. Watts NB, Bilezikian JP, Usiskin K, Edwards R, Desai M, Law G, Meininger G. Effects of canagliflozin on fracture risk in patients with type 2 diabetes mellitus. J Clin Endocrinol Metab. 2016;101:157–66.

    Article  CAS  PubMed  Google Scholar 

  183. Shubrook JH, Bokaie BB, Adkins SE. Empagliflozin in the treatment of type 2 diabetes: evidence to date. Drug Des Devel Ther. 2015;9:5793–803.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. Shahinfar S, Lyle PA, Zhang Z, Keane WF, Brenner BM. Losartan: lessons learned from the RENAAL study. Expert Opin Pharmacother. 2006;7:623–30.

    Article  CAS  PubMed  Google Scholar 

  185. Thomas MC, Cooper ME, Shahinfar S, Brenner BM. Dialysis delayed is death prevented: a clinical perspective on the RENAAL study. Kidney Int. 2003;63:1577–9.

    Article  PubMed  Google Scholar 

  186. Cao Z, Cooper ME. Efficacy of renin-angiotensin system (RAS) blockers on cardiovascular and renal outcomes in patients with type 2 diabetes. Acta Diabetol. 2012;49:243–54.

    Article  CAS  PubMed  Google Scholar 

  187. Perkovic V, Jardine MJ, Neal B, et al. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med. 2019;380:2295–306.

    Article  CAS  PubMed  Google Scholar 

  188. Wanner C, Inzucchi SE, Lachin JM, et al. Empagliflozin and progression of kidney disease in type 2 diabetes. N Engl J Med. 2016;375:323–34.

    Article  CAS  PubMed  Google Scholar 

  189. McMurray JJV, Solomon SD, Inzucchi SE, et al. Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med. 2019;NEJMoa1911303

    Google Scholar 

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Authors and Affiliations

  1. Nephrology Research Group, Vall d’Hebron Institut de Recerca (VHIR), Department of Nephrology, Vall d’Hebron Hospital Universitari, Barcelona, Spain

    Maria Jose Soler & Conxita Jacobs-Cachá

  2. Department of Medicine IV, Renal Division, Hospital of the Ludwig Maximilians University, Munich, Germany

    Manga Motrapu & Hans-Joachim Anders

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  1. Maria Jose Soler
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  2. Conxita Jacobs-Cachá
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  4. Hans-Joachim Anders
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  1. Section of Nephrology, University of Illinois at Chicago/Advocate Christ Medical Center,, Oak Lawn, IL, USA

    Edgar V. Lerma

  2. Nephrology Section, Tulane University, New Orleans, LA, USA

    Vecihi Batuman

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Soler, M.J., Jacobs-Cachá, C., Motrapu, M., Anders, HJ. (2022). Pathogenesis: Hemodynamic Alterations. In: Lerma, E.V., Batuman, V. (eds) Diabetes and Kidney Disease. Springer, Cham. https://doi.org/10.1007/978-3-030-86020-2_5

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