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Introduction: We previously reported that malignant hypertension is associated with impaired capillary density of target organs. Here, we tested the hypothesis that stabilization of hypoxia-inducible factor (HIF) in a modified "preconditioning" approach prevents the development of malignant hypertension. To stabilize HIF, we employed pharmacological inhibition of HIF prolyl hydroxylases (PHD), that profoundly affect HIF metabolism. Methods: Two-kidney, one-clip renovascular hypertension (2K1C) was induced in rats; controls were sham operated. 2K1C rats received either intermittent injections of the PHD inhibitor ICA (2-(1-chloro-4-hydroxyisoquinoline-3-carboxamido) acetate) or placebo. Thirty-five days after clipping, the frequency of malignant hypertension was assessed (based on weight loss and the occurrence of characteristic vascular lesions). In addition, kidney injury was compared between all ICA treated versus all placebo treated 2K1C, regardless of the occurrence of malignant hypertension. HIF stabilization was evaluated by immunohistochemistry, and HIF target gene expression by RT-PCR. Results: Blood pressure was elevated to the same degree in ICA- and placebo-treated 2K1C compared to control rats. ICA treatment did not affect the frequency of malignant hypertension or the extent of kidney tissue fibrosis, inflammation, or capillary density. There was a trend towards higher mortality and worse kidney function in ICA-treated 2K1C rats. ICA increased the number of HIF-1α-positive renal tubular cell nuclei and induced several HIF-1 target genes. In contrast, expression of HIF-2α protein as well as HIF-2 target genes were markedly enhanced by 2K1C hypertension, irrespective of ICA treatment. Discussion: We conclude that intermittent PHD inhibition did not ameliorate severe renovascular hypertension in rats. We speculate that the unexpected strong renal accumulation of HIF-2α in renovascular hypertension, which could not be further augmented by ICA, may contribute to the lack of a benefit from PHD inhibition., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Hartner, Dambietz, Cordasic, Willam, Burzlaff, Brötsch, Daniel, Schiffer, Amann, Veelken, Schley and Hilgers.)

Bis(4-carboxylpyrazol-1-yl)acetic acid (H 3 bcpza) (2), obtained in a one-pot synthesis, contains carboxyl groups that differ in their p K a -N,N,O-coordination whereupon the peripheral carboxyl groups are not involved in metal binding. The corresponding carbonyl complexes [Mn(H 3 -N,N,O-coordination whereupon the peripheral carboxyl groups are not involved in metal binding. The corresponding carbonyl complexes [Mn(H 2 bcpza)(CO) 3 ] (4), [Re(H 2 bcpza)(CO) 3 ] (5) and [Ru(H 2 bcpza)Cl(CO) 2 ] (6a/6b) are partially soluble in water but readily soluble in PBS buffer.

The hetereoscorpionate ligands bis(pyrazol-1-yl)acetic acid (Hbpza) and bis(3,5-dimethylpyrazol-1-yl)acetic acid (Hbdmpza) are reacted with [Sn(OAc) 2 ] or [Sn(acac) 2 ] to yield the corresponding Sn(II) complexes. A single crystal X-ray determination for the in solution monomeric complex [Sn(bpza) 2 ] (1a) revealed a dinuclear molecular structure [Sn 2 (bpza) 4 ] (1b), with κ 3 -N,N,O-coordinated bpza ligands at each of the Sn(II) and two bpza ligands μ-bridging between the Sn(II) centres. The molecular structure of [Sn(bdmpza) 2 ] (2) exhibits a homoleptic bisligand complex with both ligands displaced by the free electron pair, which is proven by DFT calculations. Oxidation of complex 2 in an attempt to synthesize a homoleptic Sn(IV) complex leads to the formation of [Sn(bdmpza)F 3 ] (3). In addition, homoleptic bisligand gallium complexes [Ga(bdmpza) 2 ][ClO 4 ] (4) and [Ga(bpza) 2 ][GaCl 4 ] (5) were prepared and characterized by 71 Ga NMR and IR spectroscopy as well as by X-ray crystallography.