Endothelial prostacyclin protects the kidney from ischemia-reperfusion injury

Abstract

Prostacyclin, or PGI2, is a product of PGI synthase (PGIS), down-stream of cyclooxygenase pathway. PGI2 has been demonstrated to play an important role in maintaining renal blood flow. Non-steroidal anti-inflammatory drugs (NSAIDs) that inhibit cyclooxygenase are reported to increase the susceptibility of patients to acute kidney injury (AKI). This study explores the role of endothelium-derived prostacyclin in ischemia-reperfusion injury (I/RI). The renal PGIS expression and PGI2 production markedly increased following I/RI. Loss of one allele of PGIS gene or selective endothelial PGIS deletion (TEK-CRE PGISfl/fl mice) caused more severe renal damage following I/RI than control mice. Iloprost, a PGI2 analog, administered 30 min before the I/R surgery, markedly attenuated the renal damage in both control mice and TEK-CRE PGISfl/fl mice. Renal p-PKA expression significantly increased after I/RI in wild-type mice but not in the PGIS deletion mice, consistent with IP receptor mediating the protective effect. Further studies showed that PGIS deficiency was associated with reduced fluorescence microsphere accumulation in the kidney following I/R. Folic acid also induced marked kidney injury; however, endothelial PGIS deletion did not worsen kidney injury compared with wild-type mice. These studies indicate that PGIS-derived PGI2 can protect the kidney from acute injury caused by ischemia and reperfusion and PGIS/PGI2 is a potential intervention target for AKI.

Downregulation of PTEN promotes podocyte endocytosis of lipids aggravating obesity-related glomerulopathy

“…By manipulating PTEN expression levels in cultured podocytes, we further demonstrated that PTEN maintains cofilin-1 activity through the dephosphorylation of cofilin-1, which blocks F-actin formation, preventing the excessive uptake of lipids. Interestingly, this response may be regulated by the PKA pathway, which is a protective signaling pathway that is activated during podocyte injury (7,14). We further validated the role of PTEN in the development of ORG in mice with podocyte-specific PTEN knockout.…”

“…Emerging evidence has shown that increased PKA signaling alleviates kidney damage and proteinuria in a variety of mouse models of kidney diseases, indicating an indispensable role for PKA in the maintenance of podocyte integrity (7,14). PKA reportedly acts as a regulator of PTEN and promotes its transcription (52).…”

Gamma-Linolenic Acid (GLA) Protects against Ionizing Radiation-Induced Damage: An In Vitro and In Vivo Study

“…Thus, AA is the precursor of pro-inflammatory PGE2, leukotrienes (LTs), and thromboxanes (TXs), and anti-inflammatory LXA4. PGI2 and PGJ2 [ 9 , 10 , 11 , 12 , 13 ]. This indicates that the ability of AA to regulate inflammation resides in the balance between the pro- and anti-inflammatory metabolites formed from it.…”

Tissue fibroblasts are a critical source of prostacyclin and anti-thrombotic protection

“…All procedures were conducted in accordance with the UK Animals (Scientific Procedures) Act ( 1986) Amendment ( 2013 ) (Langenbach et al, 1995) and global prostacyclin synthase knockout mice (Ptgis -/-) (Kirkby et al, 2020) were generated as previously described and compared to age and sex matched wild-type C57Bl/6 controls (Charles River, UK or Vital-River, China). Endothelial-specific cyclo-oxygenase-1 knockout mice (Ptgs1 flox/flox ; VEC-iCre) , endothelial/platelet-specific cyclooxygenase-1 knockout mice (Ptgs1 flox/flox ; Tie2-Cre) , endothelial/platelet-specific cyclo-oxygenase-2 knockout mice (Ptgs2 flox/flox ; Tie2-Cre) and endothelial/platelet-specific prostacyclin synthase (Ptgis flox/flox ; Tie2-Cre) (Cao et al, 2019) were generated as we have previously described. Because the VEC-iCre used to generate endothelial cyclo-oxygenase-1 knockout mice requires activation by tamoxifen, at 4-6 weeks of age, all mice from this line were treated with tamoxifen (50mg/kg, ip, once daily for 5 days; Sigma, UK) and allowed to recover to 2 weeks before further use.…”

“…Moreover, there have been no tools available that allow the contribution of individual cell types to be assessed for prostacyclin production in intact tissues or in vivo. We have recently described mice in which cyclo-oxygeanse-1, cyclo-oxygenase -2 , or prostacyclin synthase (Cao et al, 2019) can be deleted specifically from vascular endothelial cells. These mouse models provide new tools to foster the understanding of the cellular origins of prostacyclin within tissues.…”