TY - JOUR T1 - Increased levels of renal lysophosphatidic acid in rodent models with renal disease. JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther DO - 10.1124/jpet.120.000353 SP - JPET-AR-2020-000353 AU - Takashi Hirata AU - Stanley V. Smith AU - Teisuke Takahashi AU - Noriyuki Miyata AU - Richard J. Roman Y1 - 2020/01/01 UR - http://jpet.aspetjournals.org/content/early/2020/12/04/jpet.120.000353.abstract N2 - Lysophosphatidic acid (LPA) is a bioactive lipid mediator that has been implicated in the pathophysiology of kidney disease. However, few studies have attempted to measure changes in the levels of various LPA species in the kidney following the development of renal disease. The present study measured the renal LPA levels during the development of kidney disease in rat models of hypertension, diabetes, and obstructive nephropathy, using liquid chromatography/mass spectrometry/mass spectrometry (LC/MS/MS). LPA levels (sum of 16:0, 18:0, 18:1, 18:2, and 20:4 LPA) were higher in the renal cortex of hypertensive Dahl salt-sensitive (Dahl S) rats fed a high salt diet than in normotensive rats fed a low salt diet (296.6 {plus minus} 22.9 versus 196.3 {plus minus} 8.5 nmol/g protein). LPA levels were elevated in the outer medulla of the kidney of streptozotocin-induced type 1 diabetic Dahl S rats compared with control rats (624.6 {plus minus} 129.5 versus 318.8 {plus minus} 17.1 nmol/g protein). LPA levels were also higher in the renal cortex of 18-month-old, type 2 diabetic nephropathy (T2DN) rats with more severe renal injury than in 6-month-old T2DN rats (184.9 {plus minus} 20.9 versus 116.9 {plus minus} 6.0 nmol/g protein). LPA levels also paralleled the progression of renal fibrosis in the renal cortex of SD rats following unilateral ureteral obstruction (UUO). Administration of a LPA receptor antagonist, Ki16425, reduced the degree of renal fibrosis in UUO rats. These results suggest that the production of renal LPA increases during the development of renal injury and contribute to renal fibrosis. Significance Statement The present study reveals that the LPA levels increase in the kidney in rat models of hypertension, diabetes, and obstructive nephropathy and administration of a LPA receptor antagonist attenuates renal fibrosis. Therapeutic approaches that target the formation or actions of renal LPA might be renoprotective and have therapeutic potential. ER -