Nephrol Dial Transplant (1994) 9: 1716-1718 Editorial Comment Nephrology Dialysis Transplantation Plasma mevalonate and its importance in nephrology Z. A. Massy, C. Guijarro, B. L. Kasiske Department of Medicine, Division of Nephrology, Hennepin County Medical Center, University of Minnesota Medical School, Minneapolis, Minnesota, USA Key words: mesangial cell; metabolism; mevalonate; nephrotic syndrome; uraemia Introduction Mevalonic acid (MVA) is an obligate precursor in the biosynthetic pathway of a number of important com- pounds, including cholesterol. It is the product of the key regulatory, rate-limiting enzyme in sterol bio- synthesis, 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase [1]. To date, two major intracellular metabolic pathways for MVA have been described (Figure 1). The first, a sterol pathway, leads to the synthesis of cholesterol and a number of non- sterol products, all from precursors called isoprenoids Acetyl-CoA HMG-CoA HMG-CoA REDUCTASE I Mavulonata J ltop«ntanyt-pp CO, Acotoacotate SHUNT PATHWAY STEROL PATHWAY Forno, vl .pP Storoli Non-sterol Itopranolda Squalene Geranylgeranyl-PP Cholesterol Dollchol Ubiqulnone (Cotnzyme Q10) Fig. 1. The mevalonate pathways. Correspondence and offprint requests to: Ziad A. Massy MD, Division of Nephrology, Hennepin County Medical Center, 701 Park Avenue, Minneapolis, Minnesota, 55415, USA [1]. The second, or shunt pathway, diverts MVA from sterol and isoprenoid production and ultimately results in its oxidation to CO 2 [2,3]. The MVA sterol pathway has been proposed to play an important role in progressive renal disease [4,5], diabetic nephropathy [6], essential hypertension [7], and circulating lipid abnormalities. In addition prod- ucts of the MVA sterol pathway such as farnesyl and dolichol may regulate mesangial cell proliferation [4] and Na + /H + antiport activity [6] by mechanisms that are independent of cholesterol synthesis. Thus the MVA pathway is of interest to nephrologists search- ing for ways to prevent and treat renal disease. Unfortunately the direct evaluation of intracellular MVA pathway in vivo is problematic. However, circu- lating MVA is accessible to in-vivo measurement, and alterations in circulating MVA may indirectly reflect changes in intracellular MVA and thus provide a means to study this pathway in patients with renal disease. Plasma MVA metabolism Levels of MVA can be detected in animal and human plasma [8]. The plasma MVA concentrations are prob- ably determined by the balance between MVA produc- tion, which is driven by intracellular MVA synthesis in response to factors that regulate HMG-CoA reduc- tase activity [1], and its metabolism. The liver appears to be the main source of plasma MVA production [8]. The kidneys are the major site for the metabolism of circulating MVA via both sterol and shunt pathways [9]. However, the liver and intestine also participate in the metabolism of circulating MVA [10,11]. In addition, a fraction of circulating MVA presented to the kidney is excreted in the urine unchanged [12]. Mevalonate handling by the kidney has not been extensively evaluated. In animal models, conversion of MVA to squalene and sterol in the kidney is confined almost entirely to the proximal and distal convoluted tubules in the cortex. Little activity is present in the glomerulus [13]. Circulating MVA metabolism is different between species. In the rat 85% of this meta- bolism occurs in the renal tissues [9], while in the O 1994 European Dialysis and Transplant Association-European Renal Association Downloaded from https://academic.oup.com/ndt/article-abstract/9/12/1716/1834217 by guest on 22 May 2020