Key result
Malignant 2K1C hypertension increases renal MMP2 expression ~2-fold compared to benign hypertension.
Why the study?
Previous RNA-sequencing analysis indicated differential expression of matrix metalloproteases between malignant and benign 2-kidney-1-clip hypertension, prompting a detailed investigation into MMP regulation, immunohistochemistry, and gelatinase activity.
Does malignant renovascular hypertension induce differential expression of matrix metalloproteases and localized gelatinase activity in renal vascular lesions compared to benign hypertension and sham controls in rats?
Does malignant renovascular hypertension induce differential expression of matrix metalloproteases and localized gelatinase activity in renal vascular lesions compared to benign hypertension and sham controls in rats?
In rat models of malignant hypertension, MMP2 is upregulated and co-localizes with gelatinase activity specifically within severe renal vascular lesions, whereas MMP9 expression is downregulated, suggesting a distinct pathogenic role for MMP2 in malignant hypertensive vascular injury.
MMP2 may mark malignant hypertensive renal vascular injury; hypothesis-generating for MMP-targeted therapies in humans.
We previously reported a RNASeq analysis comparing kidney injury in malignant 2-kidney-1-clip hypertension versus the “benign” form of hypertension. RNAseq pointed to differential expression of many matrix metalloproteases (MMPs). We now investigated the regulation of MMP expression, immunohistochemistry and gelatinase activity in more detail. Mean blood pressure was elevated in benign hypertension (188 ± 10 mmHg) and even more pronounced in malign hypertension (236 ± 4 mmHg), compared to sham operated controls (128 ± 9mmHg). MMP2, 7, 12, 16 and 19 expression was significantly higher in malignant compared to non-malignant hypertension. The only exception was MMP9 mRNA which decreased by 0.2-fold. Gelatinase activity was detected in vascular lesions of malignant hypertension in kidneys exposed to high blood pressure. The number of gelatinase activity lesions correlated with MMP2 expression. There was no gelatinase activity in shams, or in left (post-stenotic) kidneys of hypertensive rats. MMP2 staining was detected at vascular lesions of malignant hypertensives. MMP9 staining was observed in tubules, interstitial cells, and intact vessels but absent from malignant vascular lesions. TIMP1 and 2 were detected in tubular cells. Thus, in malignant hypertension, most MMPs are upregulated. The gelatinases MMP2 and MMP9 exhibited a strikingly divergent regulation, with MMP2 localizing to malignant vascular lesions with gelatinase activity.
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Hartner et al. (2026) studied Malignant renovascular hypertension (two-kidney-one-clip animal model) (n=40). Malignant two-kidney-one-clip (2K1C) hypertension vs. Non-malignant (benign) 2K1C hypertension and sham-operated controls was evaluated on Renal MMP2 mRNA expression (fold change in malignant vs benign hypertension) and correlation with vascular lesion gelatinase activity (Fold change 1.95 (r = 0.819 for gelatinolytic activity correlation), p=0.00031). Malignant 2K1C hypertension upregulated renal MMP2 expression by 1.95-fold compared to benign hypertension (p=0.00031), correlating strongly with vascular gelatinase activity (r=0.819, p<0.001).
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