Lysophosphatidic Acid Prevents Ischemia Reperfusion Injury but does not Prevent Tubular Dysfunction

Abstract

Lysophosphatidic acid (LPA) protects the kidneys from tissue ischemic reperfusion injury (IRI), but its impact on renal function is primarily limited to glomerular function. We estimated the status of renal function by a complete glomerular and tubular functional analysis to test the hypothesis that LPA treatment during ischemia-reperfusion (I/R) protects renal function by attenuating IRI. Male Wistar rats were subjected to bilateral kidney I/R. Along with ischemia, LPA was administered. LPA increased levels of plasma LPA, downregulated LPA2R, prevented interstitial fibronectin and TGF-β1 accumulation, and prevented a decrease in glomerular filtration rate (GFR). I/R increased urine volume and proteinuria and decreased fractional Na+ excretion (FENa) and urine osmolality. These effects were not prevented by LPA. The reduction in FENa was attributed to disruption in tubular Na+ transport and downregulation of protein kinase C (PKC) activity. LPA treatment maintained (Na++K+)ATPase activity to the control level, due to a sustained sensitivity to PLC/PKC pathway. Na+-ATPase activity was insensitivity to LPA treatment. This ineffectiveness was associated with downregulation of LPA2R, resulting in low FENa. Altogether, LPA treatment maintained normal kidney structure and prevented the reduction of glomerular function. However, even in the setting of preserved GFR, impaired tubular function may present a high risk for silent progression of kidney disease.