Skip to main content
SpringerLink
Log in

Mathematical Model for Glucose Dependence of the Local Renin–Angiotensin System in Podocytes

  • Original Article
  • Published:
Bulletin of Mathematical Biology Aims and scope Submit manuscript

Abstract

Diabetic kidney disease (DKD) is the primary cause of kidney failure. Diabetic hyperglycemia primarily damages podocyte cells. Podocytes express a local renin–angiotensin system (RAS) that produces angiotensin II (ANG II). ANG II levels are elevated by hyperglycemia, triggering podocyte injury. Quantitative descriptions of glucose dose dependency of ANG II are scarce in the literature. For better understanding of the mechanism of glycemic injury in DKD, a mathematical model is developed to describe the glucose-stimulated local RAS in podocytes. The model of the RAS signaling pathway in podocytes tracks peptides and enzymes without explicit glucose dependence. Local and global sensitivity analyses are used to identify the key parameters to be estimated in the model. Three approaches are explored to incorporate glucose dependency through linear ramp functions for the sensitive parameters. The first approach uses inferences from literature data to estimate the parameter values, while the other approaches reduce the number of assumptions by using least-squares regression to estimate all or a subset of the parameters. Physiological parameter values and RAS peptide concentrations ranges are used to discriminate between plausible models for the glucose dose dependency. This is the first model of the theory of the local RAS mechanism specific to podocyte cells to track ANG II levels in a range of glycemic conditions that may contribute to podocyte damage in DKD. The ability to track ANG II behavior could enable prediction of its downstream effects on podocytes and provide opportunities to better characterize pathophysiological features of DKD progression.

Graphical Abstract

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10
Fig. 11
Fig. 12
Fig. 13

Similar content being viewed by others

References

  • Cumin F, Le-Nguyen D, Castro B, Menard J, Corvol P (1987) Comparative enzymatic studies of human renin acting on pure natural or synthetic substrates. Biochim Biophys Acta Protein Struct Mol Enzymol 913(1):10–19

    Article  Google Scholar 

  • Danser AHJ, Admiraal PJJ, Derkx FHM, Schalekamp MADH (1998) Angiotensin I-to-II conversion in the human renal vascular bed. J Hypertens 16(12):2051–2056

    Article  Google Scholar 

  • Ding G, Reddy K, Kapasi AA, Franki N, Gibbons N, Kasinath BS, Singhal PC (2002) Angiotensin II induces apoptosis in rat glomerular epithelial cells. Am. J. Physiol. Ren. Physiol. 283(1):F173–F180

    Article  Google Scholar 

  • Durvasula RV, Shankland SJ (2008) Activation of a local renin angiotensin system in podocytes by glucose. Am J Physiol Ren Physiol 294(4):F830–F839

    Article  Google Scholar 

  • Garg P, Holzman LB (2012) Podocytes: gaining a foothold. Exp Cell Res 318(9):955–963

    Article  Google Scholar 

  • Hsu HH, Hoffmann S, Endlich N, Velic A, Schwab A, Weide T, Schlatter E, Pavenstädt H (2008) Mechanisms of angiotensin II signaling on cytoskeleton of podocytes. J Mol Med 86(12):1379–1394

    Article  Google Scholar 

  • Lewis EJ, Hunsicker LG, Bain RP, Rohde RD (1993) The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. N Engl J Med 329(20):1456–1462

    Article  Google Scholar 

  • Liebau MC, Lang D, Böhm J, Endlich N, Bek MJ, Witherden I, Mathieson PW, Saleem MA, Pavenstädt H, Fischer KG (2006) Functional expression of the renin-angiotensin system in human podocytes. Am J Physiol Ren Physiol 290(3):F710–F719

    Article  Google Scholar 

  • Lo A, Beh J, De Leon H, Hallow MK, Ramakrishna R, Rodrigo M, Sarkar A, Sarangapani R, Georgieva A (2011) Using a systems biology approach to explore hypotheses underlying clinical diversity of the renin angiotensin system and the response to antihypertensive therapies. In: Kimko HHC, Peck CC (eds) Clinical trial simulations. Springer, New York, pp 457–482

    Chapter  Google Scholar 

  • Lopez-Novoa JM, Martinez-Salgado C, Rodriguez-Pena AB, Lopez-Hernandez FJ (2010) Common pathophysiological mechanisms of chronic kidney disease: therapeutic perspectives. Pharmacol Ther 128(1):61–81

    Article  Google Scholar 

  • Marino S, Hogue IB, Ray CJ, Kirschner DE (2008) A methodology for performing global uncertainty and sensitivity analysis in systems biology. J Theor Biol 254(1):178–196

    Article  MathSciNet  Google Scholar 

  • Márquez E, Riera M, Pascual J, Soler MJ (2015) Renin-angiotensin system within the diabetic podocyte. Am J Physiol Ren Physiol 308(1):F1–F10

    Article  Google Scholar 

  • Nijenhuis T, Sloan AJ, Hoenderop JGJ, Flesche J, van Goor H, Kistler AD, Bakker M, Bindels RJM, de Boer RA, Möller CC, Hamming I, Navis G, Wetzels JFM, Berden JHM, Reiser J, Faul C, van der Vlag J (2011) Angiotensin II contributes to podocyte injury by increasing TRPC6 expression via an NFAT-mediated positive feedback signaling pathway. Am J Pathol 179(4):1719–1732

    Article  Google Scholar 

  • Pavenstädt H, Kriz W, Kretzler M (2003) Cell biology of the glomerular podocyte. Physiol Rev 83(1):253–307

    Article  Google Scholar 

  • Pilvankar MR, Higgins MA, Ford Versypt AN (2017) glucoseRASpodocytes. https://doi.org/10.5281/zenodo.806015. http://github.com/ashleefv/glucoseRASpodocytes. Accessed 17 June 2011

  • Praet SF, Manders RJ, Meex RC, Lieverse A, Stehouwer CD, Kuipers H, Keizer HA, Van Loon LJ (2006) Glycaemic instability is an underestimated problem in type ii diabetes. Clin Sci 111(2):119–126

    Article  Google Scholar 

  • Remuzzi G, Benigni A, Remuzzi A (2006) Mechanisms of progression and regression of renal lesions of chronic nephropathies and diabetes. J Clin Investig 116(2):288–296

    Article  Google Scholar 

  • Sachetelli S, Liu Q, Zhang SL, Liu F, Hsieh TJ, Brezniceanu ML, Guo DF, Filep JG, Ingelfinger JR, Sigmund CD, Hamet P, Chan JSD (2006) RAS blockade decreases blood pressure and proteinuria in transgenic mice overexpressing rat angiotensinogen gene in the kidney. Kidney Int 69(6):1016–1023

    Article  Google Scholar 

  • Saran R, Li Y, Robinson B, Ayanian J, Balkrishnan R, Bragg-Gresham J, Chen JTL, Cope E, Gipson D, He K, Herman W, Heung M, Hirth RA, Jacobsen SS, Kalantar-Zadeh K, Kovesdy CP, Leichtman AB, Lu Y, Molnar MZ, Morgenstern H, Nallamothu B, OHare AM, Pisoni R, Plattner B, Port FK, P Rao, Rhee CM, Schaubel DE, Selewski DT, Shahinian V, Sim JJ, Song P, Streja E, Tamura MK, Tentori F, Eggers PW, Agodoa LYC, Abbott KC (2015) US renal data system 2014 annual data report: epidemiology of kidney disease in the United States. Am J Kidney Dis 66(S1):S1–S306

    Google Scholar 

  • Siu B, Saha J, Smoyer WE, Sullivan KA, Brosius FC (2006) Reduction in podocyte density as a pathologic feature in early diabetic nephropathy in rodents: prevention by lipoic acid treatment. BMC Nephrol 7(1):1

    Article  Google Scholar 

  • Susztak K, Raff AC, Schiffer M, Böttinger EP (2006) Glucose-induced reactive oxygen species cause apoptosis of podocytes and podocyte depletion at the onset of diabetic nephropathy. Diabetes 55(1):225–233

    Article  Google Scholar 

  • Tschöpe C, Seidl U, Reinecke A, Riester U, Graf K, Schultheiss HP, Hilgenfeldt U, Unger T (2003) Kinins are involved in the antiproteinuric effect of angiotensin-converting enzyme inhibition in experimental diabetic nephropathy. Int Immunopharmacol 3(3):335–344

    Article  Google Scholar 

  • Velez JCQ, Bland AM, Arthur JM, Raymond JR, Janech MG (2007) Characterization of renin-angiotensin system enzyme activities in cultured mouse podocytes. Am J Physiol Ren Physiol 293(1):F398–F407

    Article  Google Scholar 

  • Weil EJ, Lemley KV, Mason CC, Yee B, Jones LI, Blouch K, Lovato T, Richardson M, Myers BD, Nelson RG (2012) Podocyte detachment and reduced glomerular capillary endothelial fenestration promote kidney disease in type 2 diabetic nephropathy. Kidney Int 82(9):1010–1017

    Article  Google Scholar 

  • Wharram BL, Goyal M, Wiggins JE, Sanden SK, Hussain S, Filipiak WE, Saunders TL, Dysko RC, Kohno K, Holzman LB, Wiggins RC (2005) Podocyte depletion causes glomerulosclerosis: Diphtheria toxin-induced podocyte depletion in rats expressing human diphtheria toxin receptor transgene. J Am Soc Nephrol 16(10):2941–2952

    Article  Google Scholar 

  • Wiggins JE, Goyal M, Sanden SK, Wharram BL, Shedden KA, Misek DE, Kuick RD, Wiggins RC (2005) Podocyte hypertrophy, adaptation, and decompensation associated with glomerular enlargement and glomerulosclerosis in the aging rat: Prevention by calorie restriction. J Am Soc Nephrol 16(10):2953–2966

    Article  Google Scholar 

  • Xu ZG, Yoo TH, Ryu DR, Park HC, Ha SK, Han DS, Adler SG, Natarajan R, Kang SW (2005) Angiotensin II receptor blocker inhibits p27Kip1 expression in glucose-stimulated podocytes and in diabetic glomeruli. Kidney Int 67(3):944–952

    Article  Google Scholar 

  • Yadav A, Vallabu S, Arora S, Tandon P, Slahan D, Teichberg S, Singhal PC (2010) ANG II promotes autophagy in podocytes. Am J Physiol Cell Physiol 299(2):C488–C496

    Article  Google Scholar 

  • Yoo TH, Li JJ, Kim JJ, Jung DS, Kwak SJ, Ryu DR, Choi HY, Kim JS, Kim HJ, Han SH, Lee JE, Han DS, Kang SW (2007) Activation of the renin-angiotensin system within podocytes in diabetes. Kidney Int 71(10):1019–1027

    Article  Google Scholar 

Download references

Acknowledgements

This work supported in part by an award from the Harold Hamm Diabetes Center at the University of Oklahoma Health Sciences Center.

Author information

Authors and Affiliations

  1. School of Chemical Engineering, Oklahoma State University, Stillwater, OK, 74078, USA

    Minu R. Pilvankar, Michele A. Higgins & Ashlee N. Ford Versypt

  2. Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA

    Ashlee N. Ford Versypt

Authors
  1. Minu R. Pilvankar
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Michele A. Higgins
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ashlee N. Ford Versypt
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ashlee N. Ford Versypt.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Pilvankar, M.R., Higgins, M.A. & Ford Versypt, A.N. Mathematical Model for Glucose Dependence of the Local Renin–Angiotensin System in Podocytes. Bull Math Biol 80, 880–905 (2018). https://doi.org/10.1007/s11538-018-0408-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11538-018-0408-4

Keywords

Search

Navigation