A 12-lipoxygenase product, 12-hydroxyeicosatetraenoic acid, is increased in diabetics with incipient and early renal disease.

Abstract

Earlier studies in diabetic animal models or ex vivo from diabetics suggest a deficiency in prostacyclin (PGI2) production and an increase in an alternate arachidonic acid metabolite, 12-hydroxyeicosatetraenoic acid (12-HETE), which stimulates angiogenesis, mitogenesis, and inhibits renin secretion. We studied the urinary excretion rate of 6-keto-PGF1 alpha (a stable metabolite of PGI2) and 12-HETE in controls and 42 noninsulin-dependent diabetes mellitus (NIDDM) patients with normal renal function and those with micro- or macroalbuminuria/hyporeninemic hypoaldosteronism (HH). The 2 eicosanoids were measured in urine using previously described high pressure liquid chromatography and RIA methods. Normal subjects and patients with NIDDM and microalbuminuria were infused with low dose calcium infusions that stimulate prostacyclin production in normal subjects. The PGI2 excretion rate of NIDDM patients with normal renal function was not different from that of controls (143 +/- 17 vs. 118 +/- 34 ng/g creatinine), but was reduced in those with microalbuminuria (75 +/- 10) and in macroalbuminuria patients (48 +/- 7; P < 0.01). In contrast, 12-HETE was increased in diabetics with normal renal function as well as in those with micro- or macroalbuminuria patients (69 +/- 18 vs. 250 +/- 62 vs. 226 +/- 60 and 404 +/- 131 ng/g creatinine; P < 0.01). Calcium did not stimulate PGI2, but increased 12-HETE in diabetics with microalbuminuria in contrast to levels in normal subjects. HH patients excreted less PGI2 (as previously reported), but had increased 12-HETE. HETE/PGI2 ratios further demonstrated these changes in the various groups. In a nondiabetic hypertensive microalbuminuria group, 12-HETE excretion was normal (73 +/- 28 ng/g creatinine). We conclude that the lipoxygenase product 12-HETE is increased early in the diabetic process, whereas PGI2 production is progressively impaired in NIDDM. These changes may play a role in the vascular disease of diabetes and partially explain the HH syndrome.

The Oxidized Lipid and Lipoxygenase Product 12(S)-Hydroxyeicosatetraenoic Acid Induces Hypertrophy and Fibronectin Transcription in Vascular Smooth Muscle Cells via p38 MAPK and cAMP Response Element-binding Protein Activation

“…Increased levels of 12(S)-HETE have been observed in hypertensive and diabetic patients (50,51). The LO pathway has been implicated in the oxidation of low density lipoprotein to its atherogenic form and in the pathogenesis of atherosclerosis (52)(53)(54).…”

Physiologic and pathophysiologic roles of lipid mediators in the kidney

“…149-151 12/ 15-LO levels are increased in the glomeruli of experimental diabetic animals. [151][152][153] High glucose has been shown to directly increase 12/15-LO expression in cultured mesangial cells. 152 The 12/15 LO pathway has been shown to be a critical mediator of TGFb and ANG II-induced mesangial cell hypertrophy and extracellular matrix accumulation.…”

Inflammatory mechanisms of diabetic complications

“…Patients with type 2 diabetes have markedly increased urinary concentrations of the 12/15-LO product 12(S)-HETE compared with nondiabetic control subjects [29]. Similarly, vascular smooth muscle cells and human aortic endothelial cells cultured under high glucose conditions demonstrate significant increases in the production of 12(S)-HETE and 15(S)-HETE, suggesting that states of high glucose independently stimulate activation of inflammatory pathways [20••,30].…”