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Abstract: TH-PO964

Pericyte-Myofibroblast Transition Induced Tubulo-Interstitial Injury in a Novel Renal Venous Congestion Rat Model

Session Information

Category: Pathology and Lab Medicine

  • 1501 Pathology and Lab Medicine: Basic

Authors

  • Hirose, Takuo, Tohoku Medical and Pharmaceutical University, Sendai, Japan
  • Shimada, Satoshi, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
  • Takahashi, Chika, Tohoku Medical and Pharmaceutical University, Sendai, Japan
  • Sato, Emiko, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
  • Kinugasa, Satoshi, Tohoku Medical and Pharmaceutical University, Sendai, Japan
  • Ito, Sadayoshi, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
  • Mori, Takefumi, Tohoku Medical and Pharmaceutical University, Sendai, Japan
Background

Increased central venous pressure in congestive heart failure is responsible for renal dysfunction. However, the knowledge of the underlying mechanisms is limited. We hypothesized that renal interstitial hydrostatic pressure (RIHP) and expansion pressures of the vasa recta are responsible for pericyte detachment resulting renal congestion-mediated fibrosis. We created a novel rat renal congestion model to investigate the effect of renal congestion on hemodynamics and its molecular mechanisms.

Methods

The inferior vena cava (IVC) between the renal veins was ligated by suture in male Sprague-Dawley rats to increase upstream IVC pressure and induce congestion in the left kidney only.

Results

Left kidney congestion reduced renal blood flow in cortex (33.6%, 28.3 to 16.0 mL/min) and in medulla (41.8%, 11.9 to 6.9 mL/min) and glomerular filtration rate (17.2%, 1.16 to 0.20 mL/min/kg BW), and increased RIHP (1.4 fold, 12.6 to 17.6 mm Hg). In the congestive kidneys, hypoxia was observed in the medullary thick ascending limb of Henle. Tubulointerstitial injury, podocyte injury, albuminuria, and reduced creatinine clearance were observed in the congestive kidneys. Molecules related to extracellular matrix expansion, tubular injury, and focal adhesion were upregulated in microarray analysis. Renal decapsulation ameliorated the tubulointerstitial injury (mRNA expression of Kim1 15.3 to 4.3 A.U., αSma 5.3 to 2.8 A.U.). Electron microscopy captured pericyte detachment in the congestive kidneys. Transgelin and platelet-derived growth factor receptors (PDGFRs), as indicators of pericyte-myofibroblast transition, were upregulated in the pericytes and the adjacent interstitium. Imatinib, a PDGFR inhibitor, ameliorated the interstitial injury.

Conclusion

Our results reveal a novel mechanism of worsening renal function associated with congestive heart failure, and provide a new therapeutic candidate based on a better understanding of the pericyte-myofibroblast transition.