• 1. Lulich J, Osborne C, O'Brien T, et al. Feline renal failure: questions, answers, questions. Compend Contin Educ Pract Vet 1992;14:127153.

    • Search Google Scholar
    • Export Citation
  • 2. Marino CL, Lascelles BD, Vaden SL, et al. Prevalence and classification of chronic kidney disease in cats randomly selected from four age groups and in cats recruited for degenerative joint disease studies. J Feline Med Surg 2014;16:465472.

    • Search Google Scholar
    • Export Citation
  • 3. Brown CA, Elliott J, Schmiedt CW, et al. Chronic kidney disease in aged cats: clinical features, morphology, and proposed pathogeneses. Vet Pathol 2016;53:309326.

    • Search Google Scholar
    • Export Citation
  • 4. Chakrabarti S, Syme HM, Brown CA, et al. Histomorphometry of feline chronic kidney disease and correlation with markers of renal dysfunction. Vet Pathol 2013;50:147155

    • Search Google Scholar
    • Export Citation
  • 5. McLeland SM, Cianciolo RE, Duncan CG, et al. A comparison of biochemical and histopathologic staging in cats with chronic kidney disease. Vet Pathol 2015;52:524534.

    • Search Google Scholar
    • Export Citation
  • 6. Brown CA, Rissi DR, Dickerson VM, et al. Chronic renal changes after a single ischemic event in an experimental model of feline chronic kidney disease. Vet Pathol 2019;56:536543

    • Search Google Scholar
    • Export Citation
  • 7. Schmiedt CW, Brainard BM, Hinson W, et al. Unilateral renal ischemia as a model of acute kidney injury and renal fibrosis in cats. Vet Pathol 2016;53:87101.

    • Search Google Scholar
    • Export Citation
  • 8. DiBartola SP, Rutgers HC, Zack PM, et al. Clinicopathologic findings associated with chronic renal disease in cats: 74 cases (1973–1984). J Am Vet Med Assoc 1987;190:11961202.

    • Search Google Scholar
    • Export Citation
  • 9. Fine LG, Bandyopadhay D, Norman JT. Is there a common mechanism for the progression of different types of renal diseases other than proteinuria? Towards the unifying theme of chronic hypoxia. Kidney Int Suppl 2000;75:S22S26.

    • Search Google Scholar
    • Export Citation
  • 10. Fine LG, Norman JT. Chronic hypoxia as a mechanism of progression of chronic kidney diseases: from hypothesis to novel therapeutics. Kidney Int 2008;74:867872.

    • Search Google Scholar
    • Export Citation
  • 11. Palm F, Nordquist L. Renal tubulointerstitial hypoxia: cause and consequence of kidney dysfunction. Clin Exp Pharmacol Physiol 2011;38:474480.

    • Search Google Scholar
    • Export Citation
  • 12. Nangaku M, Eckardt KU. Hypoxia and the HIF system in kidney disease. J Mol Med (Berl) 2007;85:13251330.

  • 13. Leonard MO, Cottell DC, Godson C, et al. The role of HIF-1α in transcriptional regulation of the proximal tubular epithelial cell response to hypoxia. J Biol Chem 2003;278:4029640304.

    • Search Google Scholar
    • Export Citation
  • 14. Kimura K, Iwano M, Higgins DF, et al. Stable expression of HIF-1α in tubular epithelial cells promotes interstitial fibrosis. Am J Physiol Renal Physiol 2008;295:F1023F1029

    • Search Google Scholar
    • Export Citation
  • 15. Eddy AA. Molecular basis of renal fibrosis. Pediatr Nephrol 2000;15:290301.

  • 16. Catania JM, Chen G, Parrish AR. Role of matrix metalloproteinases in renal pathophysiologies. Am J Physiol Renal Physiol 2007;292:F905F911.

    • Search Google Scholar
    • Export Citation
  • 17. Tan RJ, Liu Y. Matrix metalloproteinases in kidney homeostasis and diseases. Am J Physiol Renal Physiol 2012;302:F1351F1361.

  • 18. Arata S, Ohmi A, Mizukoshi F, et al. Urinary transforming growth factor-β1 in feline chronic renal failure. J Vet Med Sci 2005;67:12531255.

    • Search Google Scholar
    • Export Citation
  • 19. Kang D-H, Johnson RJ. Vascular endothelial growth factor: a new player in the pathogenesis of renal fibrosis. Curr Opin Nephrol Hypertens 2003;12:4349.

    • Search Google Scholar
    • Export Citation
  • 20. Habenicht LM, Webb TL, Clauss LA, et al. Urinary cytokine levels in apparently healthy cats and cats with chronic kidney disease. J Feline Med Surg 2013;15:99104.

    • Search Google Scholar
    • Export Citation
  • 21. Riedel J, Badewien-Rentzsch B, Kohn B, et al. Characterization of key genes of the renin-angiotensin system in mature feline adipocytes and during in vitro adipogenesis. J Anim Physiol Anim Nutr (Berl) 2016;100:11391148.

    • Search Google Scholar
    • Export Citation
  • 22. Kessler Y, Helfer-Hungerbuehler AK, Cattori V, et al. Quantitative TaqMan real-time PCR assays for gene expression normalisation in feline tissues. BMC Mol Biol 2009;10:106.

    • Search Google Scholar
    • Export Citation
  • 23. Agaoglu OK, Agaoglu AR, Guzeloglu A, et al. Expression of hypoxia-inducible factors and vascular endothelial growth factor during pregnancy in the feline uterus. Theriogenology 2015;84:2433.

    • Search Google Scholar
    • Export Citation
  • 24. Agaoglu OK, Agaoglu AR, Guzeloglu A, et al. Gene expression profiles of some cytokines, growth factors, receptors, and enzymes (GM-CSF, IFNγ, MMP-2, IGF-II, EGF, TGF-β, IGF-IIR) during pregnancy in the cat uterus. Theriogenology 2016;85:638644.

    • Search Google Scholar
    • Export Citation
  • 25. Bustin SA, Benes V, Garson JA, et al. The MIQE guidelines: minimum information for publication of quantitative real-time PCR experiments. Clin Chem 2009;55:611622.

    • Search Google Scholar
    • Export Citation
  • 26. Vandesompele J, De Preter K, Pattyn F, et al. Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes. Genome Biol 2002;3:research0034.1.

    • Search Google Scholar
    • Export Citation
  • 27. Ye J, Coulouris G, Zaretskaya I, et al. Primer-BLAST: a tool to design target-specific primers for polymerase chain reaction. BMC Bioinformatics 2012;13:134.

    • Search Google Scholar
    • Export Citation
  • 28. Cowgill LD, Polzin DJ, Elliott J, et al. Is progressive chronic kidney disease a slow acute kidney injury? Vet Clin North Am Small Anim Pract 2016;46:9951013.

    • Search Google Scholar
    • Export Citation
  • 29. Kaballo MA, Elsayed ME, Stack AG. Linking acute kidney injury to chronic kidney disease: the missing links. J Nephrol 2017;30:461475.

    • Search Google Scholar
    • Export Citation
  • 30. Hodgkins KS, Schnaper HW. Tubulointerstitial injury and the progression of chronic kidney disease. Pediatr Nephrol 2012;27:901909.

  • 31. Mimura I, Nangaku M. The suffocating kidney: tubulointerstitial hypoxia in end-stage renal disease. Nat Rev Nephrol 2010;6:667678.

  • 32. Gifford FJ, Gifford RM, Eddleston M, et al. Endemic nephropathy around the world. Kidney Int Rep 2017;2:282292.

  • 33. Weaver VM, Fadrowski JJ, Jaar BG. Global dimensions of chronic kidney disease of unknown etiology (CKDu): a modern era environmental and/or occupational nephropathy? BMC Nephrol 2015;16:145.

    • Search Google Scholar
    • Export Citation
  • 34. Joyce E, Glasner P, Ranganathan S, et al. Tubulointerstitial nephritis: diagnosis, treatment, and monitoring. Pediatr Nephrol 2017;32:577587.

    • Search Google Scholar
    • Export Citation
  • 35. Bleyer AJ, Kidd K, Živná M, et al. Autosomal dominant tubulointerstitial kidney disease. Adv Chronic Kidney Dis 2017;24:8693.

  • 36. Lawson JS, Liu H-H, Syme HM, et al. The cat as a naturally occurring model of renal interstitial fibrosis: characterisation of primary feline proximal tubular epithelial cells and comparative pro-fibrotic effects of TGF-β1. PLoS One 2018;13:e0202577.

    • Search Google Scholar
    • Export Citation
  • 37. Norman JT, Fine LG. Intrarenal oxygenation in chronic renal failure. Clin Exp Pharmacol Physiol 2006;33:989996.

  • 38. Palm F, Nordquist L. Renal oxidative stress, oxygenation, and hypertension. Am J Physiol Regul Integr Comp Physiol 2011;301:R1229R1241.

    • Search Google Scholar
    • Export Citation
  • 39. Haase VH. Hypoxia-inducible factor signaling in the development of kidney fibrosis. Fibrogenesis Tissue Repair 2012;5 (suppl 1): S16.

    • Search Google Scholar
    • Export Citation
  • 40. Semenza GL. Regulation of mammalian O2 homeostasis by hypoxia-inducible factor 1. Annu Rev Cell Dev Biol 1999;15:551578.

  • 41. Higgins DF, Kimura K, Bernhardt WM, et al. Hypoxia promotes fibrogenesis in vivo via HIF-1 stimulation of epithelial-to-mesenchymal transition. J Clin Invest 2007;117:38103820.

    • Search Google Scholar
    • Export Citation
  • 42. Chakraborti S, Mandal M, Das S, et al. Regulation of matrix metalloproteinases: an overview. Mol Cell Biochem 2003;253:269285.

  • 43. Giannandrea M, Parks WC. Diverse functions of matrix metalloproteinases during fibrosis. Dis Model Mech 2014;7:193203.

  • 44. Eddy AA. Overview of the cellular and molecular basis of kidney fibrosis. Kidney Int Suppl (2011) 2014;4:28.

  • 45. Zeisberg M, Neilson EG. Mechanisms of tubulointerstitial fibrosis. J Am Soc Nephrol 2010;21:18191834.

  • 46. Ke B, Fan C, Yang L, et al. Matrix metalloproteinases-7 and kidney fibrosis (Erratum published in Front Physiol 2017;8:192). Front Physiol 2017;8:21.

    • Search Google Scholar
    • Export Citation
  • 47. Chung AW, Yang HH, Sigrist MK, et al. Matrix metalloproteinase-2 and −9 exacerbate arterial stiffening and angiogenesis in diabetes and chronic kidney disease. Cardiovasc Res 2009;84:494504.

    • Search Google Scholar
    • Export Citation
  • 48. Musiał K, Zwolinska D. Matrix metalloproteinases (MMP-2,9) and their tissue inhibitors (TIMP-1,2) as novel markers of stress response and atherogenesis in children with chronic kidney disease (CKD) on conservative treatment. Cell Stress Chaperones 2011;16:97103.

    • Search Google Scholar
    • Export Citation
  • 49. Zhou D, Tian Y, Sun L, et al. Matrix metalloproteinase-7 is a urinary biomarker and pathogenic mediator of kidney fibrosis. J Am Soc Nephrol 2017;28:598611.

    • Search Google Scholar
    • Export Citation
  • 50. Kang DH, Kanellis J, Hugo C, et al. Role of the microvascular endothelium in progressive renal disease. J Am Soc Nephrol 2002;13:806816.

    • Search Google Scholar
    • Export Citation
  • 51. Williams TL, Elliott J, Syme HM. Association between urinary vascular endothelial growth factor excretion and chronic kidney disease in hyperthyroid cats. Res Vet Sci 2014;96:436441.

    • Search Google Scholar
    • Export Citation
  • 52. Guay C, Regazzi R. Exosomes as new players in metabolic organ cross-talk. Diabetes Obes Metab 2017;19 (suppl 1):137146.

  • 53. White LE, Hassoun HT. Inflammatory mechanisms of organ crosstalk during ischemic acute kidney injury. Int J Nephrol 2012;2012:505197.

  • 54. Meldrum KK, Meldrum DR, Meng X, et al. TNF-α-dependent bilateral renal injury is induced by unilateral renal ischemia-reperfusion. Am J Physiol Heart Circ Physiol 2002;282:H540H546.

    • Search Google Scholar
    • Export Citation
  • 55. Kato J, Nakayama M, Zhu WJ, et al. Ischemia/reperfusion of unilateral kidney exaggerates aging-induced damage to the heart and contralateral kidney. Nephron Exp Nephrol 2014;126:183190.

    • Search Google Scholar
    • Export Citation

Advertisement

Profibrotic gene transcription in renal tissues from cats with ischemia-induced chronic kidney disease

Bianca N. Lourenço DVM, PhD1, Amanda E. Coleman DVM1, Chad W. Schmiedt DVM1, Cathy A. Brown VMD, PhD2, Daniel R. Rissi DVM, PhD2, James B. Stanton DVM, PhD2, Steeve Giguère DVM, PhD3, Roy D. Berghaus DVM, PhD4, Scott A. Brown VMD, PhD1,5, and Jaime L. Tarigo DVM, PhD2
View More View Less
  • 1 1Department of Small Animal Medicine and Surgery, College of Veterinary Medicine, University of Georgia, Athens, GA 30602.
  • | 2 2Department of Pathology, College of Veterinary Medicine, University of Georgia, Athens, GA 30602.
  • | 3 3Department of Large Animal Medicine, College of Veterinary Medicine, University of Georgia, Athens, GA 30602.
  • | 4 4Department of Population Health, College of Veterinary Medicine, University of Georgia, Athens, GA 30602.
  • | 5 5Department of Physiology and Pharmacology, College of Veterinary Medicine, University of Georgia, Athens, GA 30602.

Abstract

OBJECTIVE

To characterize transcription of profibrotic mediators in renal tissues of cats with ischemia-induced chronic kidney disease (CKD).

SAMPLE

Banked renal tissues from 6 cats with experimentally induced CKD (RI group) and 8 healthy control cats.

PROCEDURES

For cats of the RI group, both kidneys were harvested 6 months after ischemia was induced for 90 minutes in 1 kidney. For control cats, the right kidney was evaluated. All kidney specimens were histologically examined for fibrosis, inflammation, and tubular atrophy. Renal tissue homogenates underwent reverse transcription quantitative PCR assay evaluation to characterize gene transcription of hypoxia-inducible factor-1α (HIF-1α), matrix metalloproteinase (MMP)-2, MMP-7, MMP-9, tissue inhibitor of metalloproteinase-1 (TIMP-1), transforming growth factor-β1, and vascular endothelial growth factor A. Gene transcription and histologic lesions were compared among ischemic and contralateral kidneys of the RI group and control kidneys.

RESULTS

Ischemic kidneys had greater transcript levels of MMP-7, MMP-9, and transforming growth factor-β1 relative to control kidneys and of MMP-2 relative to contralateral kidneys. Transcription of TIMP-1 was upregulated and that of vascular endothelial growth factor A was downregulated in ischemic and contralateral kidneys relative to control kidneys. Transcription of HIF-1α did not differ among kidney groups. For ischemic kidneys, there were strong positive correlations between transcription of HIF-1α, MMP-2, MMP-7, and TIMP-1 and severity of fibrosis.

CONCLUSIONS AND CLINICAL RELEVANCE

Transcription of genes involved in profibrotic pathways remained altered in both kidneys 6 months after transient renal ischemia. This suggested that a single unilateral renal insult can have lasting effects on both kidneys.

Abstract

OBJECTIVE

To characterize transcription of profibrotic mediators in renal tissues of cats with ischemia-induced chronic kidney disease (CKD).

SAMPLE

Banked renal tissues from 6 cats with experimentally induced CKD (RI group) and 8 healthy control cats.

PROCEDURES

For cats of the RI group, both kidneys were harvested 6 months after ischemia was induced for 90 minutes in 1 kidney. For control cats, the right kidney was evaluated. All kidney specimens were histologically examined for fibrosis, inflammation, and tubular atrophy. Renal tissue homogenates underwent reverse transcription quantitative PCR assay evaluation to characterize gene transcription of hypoxia-inducible factor-1α (HIF-1α), matrix metalloproteinase (MMP)-2, MMP-7, MMP-9, tissue inhibitor of metalloproteinase-1 (TIMP-1), transforming growth factor-β1, and vascular endothelial growth factor A. Gene transcription and histologic lesions were compared among ischemic and contralateral kidneys of the RI group and control kidneys.

RESULTS

Ischemic kidneys had greater transcript levels of MMP-7, MMP-9, and transforming growth factor-β1 relative to control kidneys and of MMP-2 relative to contralateral kidneys. Transcription of TIMP-1 was upregulated and that of vascular endothelial growth factor A was downregulated in ischemic and contralateral kidneys relative to control kidneys. Transcription of HIF-1α did not differ among kidney groups. For ischemic kidneys, there were strong positive correlations between transcription of HIF-1α, MMP-2, MMP-7, and TIMP-1 and severity of fibrosis.

CONCLUSIONS AND CLINICAL RELEVANCE

Transcription of genes involved in profibrotic pathways remained altered in both kidneys 6 months after transient renal ischemia. This suggested that a single unilateral renal insult can have lasting effects on both kidneys.

Supplementary Materials

    • Supplementary Figure S1 (PDF 1294 kb)

Contributor Notes

Deceased

Address correspondence to Dr. Tarigo (tarigo@uga.edu).