Mesenchymal stem cells (MSC) prevented the progression of renovascular hypertension, improved renal function and architecture

PLoS One. 2013 Nov 4;8(11):e78464. doi: 10.1371/journal.pone.0078464. eCollection 2013.

Abstract

Renovascular hypertension induced by 2 Kidney-1 Clip (2K-1C) is a renin-angiotensin-system (RAS)-dependent model, leading to renal vascular rarefaction and renal failure. RAS inhibitors are not able to reduce arterial pressure (AP) and/or preserve the renal function, and thus, alternative therapies are needed. Three weeks after left renal artery occlusion, fluorescently tagged mesenchymal stem cells (MSC) (2×10(5) cells/animal) were injected weekly into the tail vein in 2K-1C hypertensive rats. Flow cytometry showed labeled MSC in the cortex and medulla of the clipped kidney. MSC prevented a further increase in the AP, significantly reduced proteinuria and decreased sympathetic hyperactivity in 2K-1C rats. Renal function parameters were unchanged, except for an increase in urinary volume observed in 2K-1C rats, which was not corrected by MSC. The treatment improved the morphology and decreased the fibrotic areas in the clipped kidney and also significantly reduced renal vascular rarefaction typical of 2K-1C model. Expression levels of IL-1β, TNF-α angiotensinogen, ACE, and Ang II receptor AT1 were elevated, whereas AT2 levels were decreased in the medulla of the clipped kidney. MSC normalized these expression levels. In conclusion, MSC therapy in the 2K-1C model (i) prevented the progressive increase of AP, (ii) improved renal morphology and microvascular rarefaction, (iii) reduced fibrosis, proteinuria and inflammatory cytokines, (iv) suppressed the intrarenal RAS, iv) decreased sympathetic hyperactivity in anesthetized animals and v) MSC were detected at the CNS suggesting that the cells crossed the blood-brain barrier. This therapy may be a promising strategy to treat renovascular hypertension and its renal consequences in the near future.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood Pressure
  • Blood-Brain Barrier / cytology
  • Blood-Brain Barrier / metabolism
  • Fluorescent Dyes
  • Gene Expression
  • Hypertension, Renovascular / genetics
  • Hypertension, Renovascular / metabolism
  • Hypertension, Renovascular / pathology
  • Hypertension, Renovascular / therapy*
  • Interleukin-1beta / genetics
  • Interleukin-1beta / metabolism
  • Kidney / metabolism
  • Kidney / pathology
  • Male
  • Mesenchymal Stem Cell Transplantation*
  • Mesenchymal Stem Cells / cytology
  • Mesenchymal Stem Cells / physiology
  • Peptidyl-Dipeptidase A / genetics
  • Peptidyl-Dipeptidase A / metabolism
  • Proteinuria / genetics
  • Proteinuria / metabolism
  • Proteinuria / pathology
  • Proteinuria / therapy*
  • Rats
  • Rats, Wistar
  • Receptor, Angiotensin, Type 1 / genetics
  • Receptor, Angiotensin, Type 1 / metabolism
  • Receptor, Angiotensin, Type 2 / genetics
  • Receptor, Angiotensin, Type 2 / metabolism
  • Renal Artery / surgery
  • Renin-Angiotensin System / genetics
  • Treatment Outcome
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • Fluorescent Dyes
  • Interleukin-1beta
  • Receptor, Angiotensin, Type 1
  • Receptor, Angiotensin, Type 2
  • Tumor Necrosis Factor-alpha
  • Peptidyl-Dipeptidase A

Grant support

This work was supported by grants from the Coordenação de Aperfeiçoamento de Nível Superior (CAPES) and Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.