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  • Since all the above vascular and

    2023-12-08

    Since all the above vascular and glomerular effects contribute to blood pressure regulation, it is expected for 12/15-LOX pathway to play a role in pathogenesis of hypertension (Fig. 6). Indeed, there is evidence for alterations of the 12- and 15LOX enzymes and metabolites both in humans with essential hypertension and in various animal models of hypertension. In patients with essential hypertension urinary 12HETE excretion was found to be increased [196]. Also, a polymorphism in the human 12-LOX gene (encoding for the platelet form) is associated with essential hypertension [197]. Increased 12(S)-HETE production and 12-LOX mRNA expression was reported in the vasculature of SHR as well as other animal models of both angiotensin-dependent and renovascular hypertension [198], [199], [200]. Also, blood pressure was decreased in 12/15-LOX knockout mice that were chronically infused with angiotensin II [101]. In addition, 12-LOX inhibitors have also been shown to ameliorate hypertension in different animal models [200], [201]. Altogether the data supports a key role for 12- and 15-LOX pathway in animal and human hypertension; additional studies are needed to clearly substantiate a causative effect for this pathway in different forms of hypertension. The 12- and 15-LOX pathway is the primary LOX pathway implicated in vascular and renal injury associated with diabetes [6], [186] (Fig. 6). 12/15-LOX was detected in renal microvessels, glomeruli mesangial cells, and podocytes [188], [202], [203], [204]. Importantly, 12(S)-HETE is increased in urine of diabetic patients with early kidney disease [6], [205] and 12- and 15-LOX mRNA and protein expression increases in parallel with established markers of diabetic nephropathy [205]. 12/15-LOX expression has been increased in glomeruli of diabetic animals and glucose was shown to directly increase 12/15-LOX expression in cultured mesangial Cyclic di-GMP [203], [205], [206]. The LOX pathway is also involved in high glucose-induced monocyte adhesion to endothelial cells [120], [207]. In addition, the 12/15-LOX pathway is a critical mediator of mesangial cell hypertrophy and matrix accumulation induced by TGF-β and angiotensin II [101], [208], [209] and the effect could be blocked by LOX pharmacological inhibition or by targeted 12/15-LOX gene deletion [6], [101], [208], [209]. Cultured rat mesangial cells treated with TGFβ and angiotensin II displayed increased 12-LOX mRNA expression and formation of 12(S)-HETE [6]. There is evidence for a dual role of the LOX pathway in acute renal failure. While LOX enzymes and metabolites were shown to act as vasoconstrictive and pro-inflammatory mediators in acute and chronic renal disease, there is also evidence for a protective role of the 15-LOX pathway in acute renal failure mediated by the lipoxin family of metabolites [210] (Fig. 6). The spectrum of bioactivities reported for lipoxins suggests that they may be protective in various human renal diseases. LXA4 has been demonstrated to oppose the reduction in renal blood flow and GFR induced by LTD4 infusion, and the effect is owed to the activation of peptide-LT receptors [185], [211]. Lipoxin generation can also shift the glomerular response from inflammation to resolution and inhibition of monocyte recruitment [211]. Also lipoxins reportedly reduced PMN chemotaxis, adhesion, and migration across glomerular endothelial cells [212] and increased clearance of apoptotic PMNs from inflamed glomeruli [164]; they also inhibited mesangial cell proliferation in response to PDGF and reduced pro-inflammatory cytokine production [213], [214], [215]. Over-expression of 15-LOX in rat kidney has demonstrated a protective role in immune-mediated glomerulonephritis and is paralleled by lipoxin formation [216]. Of importance, structural analogs of LXA4 show therapeutic potential for the treatment of acute renal failure. Also, in a murine model of ischemia–reperfusion injury (IRI) the lipoxin analog 15-epi-16(FPhO)-LXA4-Me reduced PMN infiltration, preserved tubular integrity, and normalized serum creatinine levels [217]. Also, SOCS-1 and -2 were increased in IRI animals treated with the LXA4 analogue and several pro-inflammatory cytokine expression was reduced [217]. Finally, the role of LXA4 in its ability to downregulate the mesangial cell receptor tyrosine kinases in primary cultures of human mesangial cells is suggestive of a protective role of lipoxins against renal chronic inflammatory response [213], [214]. A very recent report indicates a protective role of protectins (PD1) in IRI [218]. Therapeutic or dietary amplification of PD1 formation via increase in dietary ω−3 PUFA dramatically impacts renal lipid autacoid formation and positive outcome of IRI [218].