Skip to main content

Assessment of Diabetic Nephropathy in the Akita Mouse

  • Protocol
  • First Online:
Animal Models in Diabetes Research

Part of the book series: Methods in Molecular Biology ((MIMB,volume 933))

Abstract

Akita mice have type 1 diabetes mellitus caused by a spontaneous point mutation in the Ins2 gene which leads to misfolding of insulin, resulting in pancreatic β-cell failure. Akita mice develop pronounced and sustained hyperglycemia, high levels of albuminuria, and consistent histopathological changes, suggesting that these mice may be suitable as an experimental platform for modeling diabetic nephropathy. One key feature of diabetic kidney disease in Akita mice is that the severity of renal injury is significantly influenced by genetic background. In this chapter, we describe the Akita model and present some of the experimental studies utilizing Akita mice as a model of type 1 diabetes. For example, deficiency in bradykinin receptors, endothelial nitric oxide synthase, or angiotensin-converting enzyme 2 leads to development of functionally and structurally more advanced diabetic nephropathy in these mice, while ketogenic diet has been shown to reverse kidney injury associated with diabetes. This chapter also describes the application of 24-h urine collections from mice for careful measurement of urinary albumin excretion.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Protocol
USD 49.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 84.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 159.00
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 109.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Reutens AT, Atkins RC (2011) Epidemiology of diabetic nephropathy. Contrib Nephrol 170:1–7

    Article  PubMed  Google Scholar 

  2. de Boer IH et al (2011) Temporal trends in the prevalence of diabetic kidney disease in the United States. JAMA 305:2532–2539

    Article  PubMed  Google Scholar 

  3. (2003) USRDS: the United States Renal Data System. Am J Kidney Dis 42:1–230

    Google Scholar 

  4. Chavers BM et al (1989) Glomerular lesions and urinary albumin excretion in type I diabetes without overt proteinuria. N Engl J Med 320:966–970

    Article  PubMed  CAS  Google Scholar 

  5. Dalla VM et al (2000) Structural involvement in type 1 and type 2 diabetic nephropathy. Diabetes Metab 26(Suppl 4):8–14

    Google Scholar 

  6. Breyer MD et al (2005) Mouse models of diabetic nephropathy. J Am Soc Nephrol 16:27–45

    Article  PubMed  Google Scholar 

  7. Brosius FC 3rd et al (2009) Mouse models of diabetic nephropathy. J Am Soc Nephrol 20:2503–2512

    Article  PubMed  Google Scholar 

  8. Gurley SB et al (2010) Influence of genetic background on albuminuria and kidney injury in Ins2(+/C96Y) (Akita) mice. Am J Physiol Renal Physiol 298:F788–795

    Article  PubMed  CAS  Google Scholar 

  9. Gurley SB et al (2006) Impact of genetic background on nephropathy in diabetic mice. Am J Physiol Renal Physiol 290:F214–222

    Article  PubMed  CAS  Google Scholar 

  10. Yoshioka M et al (1997) A novel locus, Mody4, distal to D7Mit189 on chromosome 7 determines early-onset NIDDM in nonobese C57BL/6 (Akita) mutant mice. Diabetes 46:887–894

    Article  PubMed  CAS  Google Scholar 

  11. Ron D (2002) Proteotoxicity in the endoplasmic reticulum: lessons from the Akita diabetic mouse. J Clin Invest 109:443–445

    PubMed  CAS  Google Scholar 

  12. Cowie CC (1993) Diabetic renal disease: racial and ethnic differences from an epidemiologic perspective. Transplant Proc 25:2426–2430

    PubMed  CAS  Google Scholar 

  13. Qi Z et al (2005) Characterization of susceptibility of inbred mouse strains to diabetic nephropathy. Diabetes 54:2628–2637

    Article  PubMed  CAS  Google Scholar 

  14. Kakoki M, Smithies O (2009) The kallikrein-kinin system in health and in diseases of the kidney. Kidney Int 75:1019–1030

    Article  PubMed  CAS  Google Scholar 

  15. Kakoki M et al (2010) Lack of both bradykinin B1 and B2 receptors enhances nephropathy, neuropathy, and bone mineral loss in Akita diabetic mice. Proc Natl Acad Sci U S A 107:10190–10195

    Article  PubMed  CAS  Google Scholar 

  16. Kakoki M et al (2004) Diabetic nephropathy is markedly enhanced in mice lacking the bradykinin B2 receptor. Proc Natl Acad Sci U S A 101:13302–13305

    Article  PubMed  CAS  Google Scholar 

  17. Rigat B et al (1990) An insertion/deletion polymorphism in the angiotensin I-converting enzyme gene accounting for half the variance of serum enzyme levels. J Clin Invest 86:1343–1346

    Article  PubMed  CAS  Google Scholar 

  18. Gurley SB, Coffman TM (2007) The renin-angiotensin system and diabetic nephropathy. Semin Nephrol 27:144–152

    Article  PubMed  CAS  Google Scholar 

  19. Lewis EJ et al (1993) The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. The Collaborative Study Group. N Engl J Med 329:1456–1462

    Article  PubMed  CAS  Google Scholar 

  20. Spillmann F et al (2002) Regulation of cardiac bradykinin B1- and B2-receptor mRNA in experimental ischemic, diabetic, and pressure-overload-induced cardiomyopathy. Int Immunopharmacol 2:1823–1832

    Article  PubMed  CAS  Google Scholar 

  21. Schremmer-Danninger E et al (1998) B1 bradykinin receptors and carboxypeptidase M are both upregulated in the aorta of pigs after LPS infusion. Biochem Biophys Res Commun 243:246–252

    Article  PubMed  CAS  Google Scholar 

  22. Ahluwalia A, Perretti M (1999) B1 receptors as a new inflammatory target. Could this B the 1? Trends Pharmacol Sci 20:100–104

    Article  PubMed  CAS  Google Scholar 

  23. Chopra B et al (2005) Expression and function of bradykinin B1 and B2 receptors in normal and inflamed rat urinary bladder urothelium. J Physiol 562:859–871

    Article  PubMed  CAS  Google Scholar 

  24. Duka I et al (2001) Vasoactive potential of the b(1) bradykinin receptor in normotension and hypertension. Circ Res 88:275–281

    Article  PubMed  CAS  Google Scholar 

  25. Futrakul N et al (2006) Early detection of endothelial injury and dysfunction in conjunction with correction of hemodynamic maladjustment can effectively restore renal function in type 2 diabetic nephropathy. Clin Hemorheol Microcirc 34:373–381

    PubMed  CAS  Google Scholar 

  26. Ignarro LJ et al (1987) Endothelium-derived relaxing factor produced and released from artery and vein is nitric oxide. Proc Natl Acad Sci U S A 84:9265–9269

    Article  PubMed  CAS  Google Scholar 

  27. Bogdan C (2001) Nitric oxide and the immune response. Nat Immunol 2:907–916

    Article  PubMed  CAS  Google Scholar 

  28. Zanchi A et al (2000) Risk of advanced diabetic nephropathy in type 1 diabetes is associated with endothelial nitric oxide synthase gene polymorphism. Kidney Int 57:405–413

    Article  PubMed  CAS  Google Scholar 

  29. Ksiazek P et al (2003) Endothelial nitric oxide synthase gene intron 4 polymorphism in type 2 diabetes mellitus. Mol Diagn 7:119–123

    Article  PubMed  Google Scholar 

  30. Ezzidi I et al (2008) Association of endothelial nitric oxide synthase Glu298Asp, 4b/a, and -786 T  >  C gene variants with diabetic nephropathy. J Diabetes Complications 22:331–338

    Article  PubMed  Google Scholar 

  31. Wang CH et al (2011) A modest decrease in endothelial NOS in mice comparable to that associated with human NOS3 variants exacerbates diabetic nephropathy. Proc Natl Acad Sci U S A 108:2070–2075

    Article  PubMed  CAS  Google Scholar 

  32. Tikellis C et al (2003) Characterization of renal angiotensin-converting enzyme 2 in diabetic nephropathy. Hypertension 41:392–397

    Article  PubMed  CAS  Google Scholar 

  33. Wysocki J et al (2006) ACE and ACE2 activity in diabetic mice. Diabetes 55:2132–2139

    Article  PubMed  CAS  Google Scholar 

  34. Ye M et al (2004) Increased ACE 2 and decreased ACE protein in renal tubules from diabetic mice: a renoprotective combination? Hypertension 43:1120–1125

    Article  PubMed  CAS  Google Scholar 

  35. Mizuiri S et al (2008) Expression of ACE and ACE2 in individuals with diabetic kidney disease and healthy controls. Am J Kidney Dis 51:613–623

    Article  PubMed  CAS  Google Scholar 

  36. Reich HN et al (2008) Decreased glomerular and tubular expression of ACE2 in patients with type 2 diabetes and kidney disease. Kidney Int 74:1610–1616

    Article  PubMed  CAS  Google Scholar 

  37. Wong DW et al (2007) Loss of angiotensin-converting enzyme-2 (Ace2) accelerates diabetic kidney injury. Am J Pathol 171:438–451

    Article  PubMed  CAS  Google Scholar 

  38. Oudit GY et al (2010) Human recombinant ACE2 reduces the progression of diabetic nephropathy. Diabetes 59:529–538

    Article  PubMed  CAS  Google Scholar 

  39. Poplawski MM et al (2011) Reversal of diabetic nephropathy by a ketogenic diet. PLoS One 6:e18604

    Article  PubMed  CAS  Google Scholar 

  40. Al-Khalifa A et al (2009) Therapeutic role of low-carbohydrate ketogenic diet in diabetes. Nutrition 25:1177–1185

    Article  PubMed  CAS  Google Scholar 

  41. Badman MK et al (2009) A very low carbohydrate ketogenic diet improves glucose tolerance in ob/ob mice independent of weight loss. Am J Physiol Endocrinol Metab 297(5):E1197–204

    Article  PubMed  CAS  Google Scholar 

  42. Chmiel-Perzynska I et al (2011) Novel aspect of ketone action: beta-hydroxybutyrate increases brain synthesis of kynurenic acid in vitro. Neurotox Res 20:40–50

    Article  PubMed  CAS  Google Scholar 

  43. Ma W, Berg J, Yellen G (2007) Ketogenic diet metabolites reduce firing in central neurons by opening K(ATP) channels. J Neurosci 27:3618–3625

    Article  PubMed  CAS  Google Scholar 

  44. Hong EG et al (2007) Nonobese, insulin-deficient Ins2Akita mice develop type 2 diabetes phenotypes including insulin resistance and cardiac remodeling. Am J Physiol Endocrinol Metab 293:E1687–1696

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Susan B. Gurley .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2012 Springer Science+Business Media, LLC

About this protocol

Cite this protocol

Chang, JH., Gurley, S.B. (2012). Assessment of Diabetic Nephropathy in the Akita Mouse. In: Joost, HG., Al-Hasani, H., Schürmann, A. (eds) Animal Models in Diabetes Research. Methods in Molecular Biology, vol 933. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-62703-068-7_2

Download citation

  • DOI: https://doi.org/10.1007/978-1-62703-068-7_2

  • Published:

  • Publisher Name: Humana Press, Totowa, NJ

  • Print ISBN: 978-1-62703-067-0

  • Online ISBN: 978-1-62703-068-7

  • eBook Packages: Springer Protocols

Publish with us

Policies and ethics