Kidney Week

Abstract: TH-PO206

Matrix Metalloprotease Activity in Vascular Lesions of Malignant Hypertensive Rats

Session Information

• Hypertension and CVD: Basic Research Findings
  October 24, 2024 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Hypertension and CVD

• 1601 Hypertension and CVD: Basic

Authors

• Hartner, Andrea, Friedrich-Alexander-Universitat Erlangen-Nurnberg, Erlangen, Bayern, Germany

Andrea Hartner, PhD

• Cordasic, Nada, Friedrich-Alexander-Universitat Erlangen-Nurnberg, Erlangen, Bayern, Germany

Nada Cordasic

• Schiffer, Mario, Friedrich-Alexander-Universitat Erlangen-Nurnberg, Erlangen, Bayern, Germany

Mario Schiffer, MD, DrMed, MBA

• Veelken, Roland, Friedrich-Alexander-Universitat Erlangen-Nurnberg, Erlangen, Bayern, Germany

Roland Veelken, MD, DrMed

• Amann, Kerstin U., Friedrich-Alexander-Universitat Erlangen-Nurnberg, Erlangen, Bayern, Germany

Kerstin U. Amann, MD

• Daniel, Christoph, Friedrich-Alexander-Universitat Erlangen-Nurnberg, Erlangen, Bayern, Germany

Christoph Daniel, PhD

• Hilgers, Karl F., Friedrich-Alexander-Universitat Erlangen-Nurnberg, Erlangen, Bayern, Germany

Karl F. Hilgers, MD, FASN

Background

In malignant hypertension (MH), far more severe kidney injury occurs than in the “benign” form (NMH) of the disease. In a previously reported RNA-Seq analysis of renal cortical tissue from a rat model of MH, we observed an altered expression of several matrix metalloproteases (MMP). We now investigated gelatinase activity localized to the characteristic vascular lesions of MH.

Methods

Renovascular hypertension in rats was induced by placing a 0.2 mm clip on the left renal artery (2K1C), controls were sham operated. To distinguish MH from NMH, we considered weight loss and typical vascular lesions (onion-skin and fibrinoid necroses). The expression of MMPs was measured by RT-PCR; immunohistochemistry was performed for MMP-2 and 9. In-situ zymography was performed to localize gelatinase activity.

Results

Mean blood pressure measured intra-arterially was elevated to a similar degree in MH (220±7 mmHg) and NMH (192±6 mmHg), compared to controls (119±2 mmHg, p<0.05). MMP-2, -7, -8, -10, -12, -16 and -19 expression were all elevated in NMH and significantly higher increased in MH. The only exception was MMP-9 mRNA which barely changed in NMH but decreased by 0.2-fold in MH (p<0.05). In situ zymography revealed gelatinase activity predominantly in preglomerular vascular lesions of MH (52.8 ± 7.2 versus 20.5 ± 6.1 per medium power field in NMH, p<0.05) in right kidneys exposed to high blood pressure. The number of these gelatinase activity lesions correlated with the glomerulosclerosis score (r=0.75, p<0.0001). There was no gelatinase activity in sham operated animals, or in left (post-stenotic) kidneys of MH or NMH. MMP-2 staining was detected in, or closely surrounding, vascular lesions (3.46 ± 0.9 MMP-2 positive lesions per 10 high power fields in MH versus 0.22 ± 0.09 in NMH and 0 in sham, p<0.05). MMP-9 staining was observed in proximal tubules, individual interstitial cells, and intact or hypertrophic preglomerular vessels but absent from malignant vascular lesions.

Conclusion

In malignant hypertension of 2K1C rats, most MMPs are upregulated, broadly consistent with enhanced tissue injury. However, the gelatinases MMP-2 and MMP-9 exhibited a strikingly divergent regulation, with MMP-2 clearly localized to malignant vascular lesions with gelatinase activity.

Funding

• Government Support – Non-U.S.