Prostaglandin E2 receptors as therapeutic targets in renal fibrosis

Prostaglandin E2 (PGE2), a lipid mediator produced by the cyclooxygenase enzyme system, is the main prostaglandin in the kidney. PGE2 is involved in various physiological and pathophysiological processes in the kidney, including renal hemodynamics, water and salt balance, and renal fibrosis—a key pathological feature of progressive kidney diseases. PGE2 functions by binding to four G-protein-coupled EP receptors (EP1 to EP4), which stimulate different intracellular signaling pathways. The intrarenal distribution of the four EP receptors as well as the different downstream signaling pathways associated with each receptor give rise to the distinct functional consequence of activating each receptor subtype. This review summarizes the current data on the renal expression of the four EP receptors and delineates the role of each receptor in renal fibrosis.

Physiology and pathophysiology of cyclooxygenase-2 and prostaglandin E2 in the kidney

The cyclooxygenase (COX) enzyme system is the major pathway catalyzing the conversion of arachidonic acid into prostaglandins (PGs). PGs are lipid mediators implicated in a variety of physiological and pathophysiological processes in the kidney, including renal hemodynamics, body water and sodium balance, and the inflammatory injury characteristic in multiple renal diseases. Since the beginning of 1990s, it has been confirmed that COX exists in 2 isoforms, referred to as COX-1 and COX-2. Even though the 2 enzymes are similar in size and structure, COX-1 and COX-2 are regulated by different systems and have different functional roles. This review summarizes the current data on renal expression of the 2 COX isoforms and highlights mainly the role of COX-2 and PGE2 in several physiological and pathophysiological processes in the kidney.

Development of intestinal ischemia/reperfusion-induced acute kidney injury in rats with or without chronic kidney disease: Cytokine/chemokine response and effect of alpha-melanocyte-stimulating hormone

BACKGROUND: The primary aim of the study was to investigate the cytokine/chemokine response in the kidney, lung, and liver following acute kidney injury (AKI). The secondary aim was to test whether alpha-melanocyte-stimulating hormone (alpha-MSH) could prevent a reduction in organ function, and attenuate the inflammatory cytokine/chemokine response within the kidney, lung, and liver following AKI in rats with or without preexisting chronic kidney disease (CKD). METHODS: A two-stage animal model, in which AKI was induced in rats with preexisting CKD, induced by 5/6 nephrectomy (Nx), was used. Six weeks later, AKI was induced by intestinal ischemia and reperfusion (IIR). Sham procedures [S(Nx) and S(IIR)] were also performed. RESULTS: Increasing levels of serum creatinine (sCr) demonstrated progressive development of CKD in response to Nx, and following IIR sCr levels increased further significantly, except in the S(Nx) group treated with alpha-MSH. However, no significant differences in the fractional increase in sCr were observed between any of the groups exposed to IIR. In kidney, lung, and liver tissue the levels of interleukin (IL)-1beta were significantly higher in rats undergoing IIR when compared to the S(IIR) and control rats. The same pattern was observed for the chemokine monocyte chemoattractant protein (MCP)-1 in lung and liver tissue. Furthermore, kidney IL-1beta and RANTES levels were significantly increased after IIR in the Nx rats compared to the S(Nx) rats. CONCLUSION: Both the functional parameters and the cytokine/chemokine response are as dramatic when AKI is superimposed onto CKD as onto non-CKD. No convincing protective effect of alpha-MSH was detected.