Attenuated glomerular arginine transport prevents hyperfiltration and induces HIF-1α in the pregnant uremic rat

Abstract

Pregnancy worsens renal function in females with chronic renal failure (CRF) through an unknown mechanism. Reduced nitric oxide (NO) generation induces renal injury. Arginine transport by cationic amino acid transporter-1 (CAT-1), which governs endothelial NO generation, is reduced in both renal failure and pregnancy. We hypothesize that attenuated maternal glomerular arginine transport promotes renal damage in CRF pregnant rats. In uremic rats, pregnancy induced a significant decrease in glomerular arginine transport and cGMP generation (a measure of NO production) compared with CRF or pregnancy alone and these effects were prevented by l-arginine. While CAT-1 abundance was unchanged in all experimental groups, protein kinase C (PKC)-α, phosphorylated PKC-α (CAT-1 inhibitor), and phosphorylated CAT-1 were significantly augmented in CRF, pregnant, and pregnant CRF animals; phenomena that were prevented by coadministrating l-arginine. α-Tocopherol (PKC inhibitor) significantly increased arginine transport in both pregnant and CRF pregnant rats, effects that were attenuated by ex vivo incubation of glomeruli with PMA (a PKC stimulant). Renal histology revealed no differences between all experimental groups. Inulin and p-aminohippurate clearances failed to augment and renal cortical expression of hypoxia inducible factor-1α (HIF-1α) significantly increased in CRF pregnant rat, findings that were prevented by arginine. These studies suggest that in CRF rats, pregnancy induces a profound decrease in glomerular arginine transport, through posttranslational regulation of CAT-1 by PKC-α, resulting in attenuated NO generation. These events provoke renal damage manifested by upregulation of renal HIF-1α and loss of the ability to increase glomerular filtration rate during gestation.

Estradiol augments while progesterone inhibits arginine transport in human endothelial cells through modulation of cationic amino acid transporter-1

“…It is widely thought that estrogen exerts protective effects on the cardiovascular system, at least in part, through augmenting NO generation by eNOS (33). We have previously shown in two experimental models of ECD, namely, aging and renal failure, that in the female gender, in contrast to males, arginine transport is not downregulated (22,(27)(28)(29)(30). The current experiments, explor- ing a positive effect of E 2 on arginine transport and the NOS system, can therefore provide a mechanism to explain the aforementioned phenomenon.…”

“…Interestingly, in two well-established experimental models of ECD (renal failure and aging), arginine transport by CAT-1 decreased only in males while females were protected (22,28). In contrast, during pregnancy, females lose the ability to maintain adequate endothelial arginine transport velocities by CAT-1, a loss that is associated with increased protein nitration possibly due to posttranslational regulation of CAT-1 by protein kinase C␣ (PKC␣) (24,30). Our current experiments, which utilized human umbilical vein endothelial cells (HUVEC), were designed to test the hypothesis that female sex hormones modulate CAT-1 activity, thus playing a role in both the gender-and pregnancy-related effects on the L-arginine-eNOS system.…”

Associations between endothelial nitric oxide synthase polymorphisms and risk of diabetic nephropathy: an updated meta-analysis

“…3,4 Decreased NO activity can be attributed to the impaired production of NO due to uncoupled receptormediated signal transduction, deficient NOS substrate L-arginine, or decreased availability of one or more cofactors essential for the optimal function of NOS. 5 Reduced NO generation induces renal injury, 6 and impaired endothelial NO generation is the major deterioration factor for progressive renal disease.…”

Association of Endothelial Nitric Oxide Synthase Glu298Asp Gene Polymorphism with the Risk of End-Stage Renal Disease

“…11 Reduced NO generation induces renal injury, 12 and impairment of endothelial NO generation is considered as the major deterioration factor for progressive renal disease. NO is produced by inducible nitric oxide synthase (iNOS).…”