Integrated Treatment of Prostaglandin E1 and Angiotensin-Converting Enzyme Inhibitor in Diabetic Kidney Disease Rats: Possible Role of Antiapoptosis in Renal Tubular Epithelial Cells

Abstract

To investigate the therapeutic mechanisms underlying prostaglandin E1 (PGE1) and angiotensin-converting enzyme inhibitor (ACEI) on reducing urinary protein in diabetic kidney disease (DKD). DKD rats were established and randomly divided into four groups: PGE1 (10 μg/kg/day) (P group), ACEI (10 mg/kg/day) (A group), combination of PGE1 with ACEI treatment (P + A group), and saline treatment group (DKD group). Untreated rats were used as normal control (N group). Urinary albumin, endothelin-1 (ET-1), angiotensin II (AngII), TUNEL assay, Masson's trichrome staining, and immunohistochemistry staining for CD68 were evaluated in all groups. Ten days after treatment, urinary albumin was significantly decreased in the P and P + A groups (p < 0.01 vs. the DKD group). At the end of 8 weeks, the albumin was still significantly reduced in the P + A group (p < 0.05 vs. the A group). ET-1 and AngII were also significantly decreased in three treatment groups (p < 0.01 vs. the DKD group), especially in the P + A group. Few cells underwent apoptosis in glomerular regions in DKD rats, while amounts of apoptotic cells were seen in tubules regions. Further, apoptosis and the areas of fibrosis in tubulointerstitial were both decreased most in the P + A group compared with the DKD group. Apoptosis of renal tubular epithelial cells may participate in the development and progression of DKD in rats. Combination of PGE1 with AGEI remarkably protects renal function compared with PGE1 or ACEI monotherapy. The potential therapeutic mechanisms of PGE1 and AGEI might be via multiple targets and, at least in part, through inhibiting the apoptosis of renal tubular epithelial cells.

Prostaglandin E1 attenuates high glucose-induced apoptosis in proximal renal tubular cells by inhibiting the JNK/Bim pathway

“…There was an elevated level of microalbuminuria in the DKD group compared with that in the sham and Unx groups on day 38 ( P < 0.05, Fig. 1d ), in accordance with previous findings in the DKD model [ 25 ]. Additionally, the level of microalbuminuria in the PGE1 group decreased compared with that in the DKD group after 10 d of PGE1 treatment, and the difference was statistically significant ( P < 0.05, Fig.…”

“…In addition, PGE1 inhibits apoptosis via the downregulation of Bax expression and the upregulation of Bcl-2 expression in neonatal rat cardiomyocytes under hypoxic conditions [ 24 ]. Previously, we found that PGE1 alleviates urinary protein levels by inhibiting the apoptosis of renal tubular epithelial cells in DKD rats [ 25 ]. Notably, illuminating how PGE1 affects proximal renal tubular apoptosis might be helpful for identifying the pharmacological mechanism of PGE1.…”

“…To induce DKD, the rats were left in a diabetic condition without any treatment for the following 4 weeks [ 28 ]. The DKD model was considered to be successfully established in animals that produced over 1.5 times more urine than they produced before the procedure and that exhibited 24-h microalbuminuria levels that were 10 times higher than those in the control group [ 25 ]. The rats in the sham and Unx groups that did not receive STZ injection were used as nondiabetic controls.…”

“…Exogenous PGE1 is a powerful vasodilator and platelet aggregation inhibitor that has a wide range of pharmacological applications. In recent years, PGE1 has been found to reduce apoptosis in other animals and tissues [ 22 – 25 ]. Our previous experiment demonstrated that PGE1 reduces the apoptosis of renal tubular cells in DKD rats [ 25 ].…”

“…In recent years, PGE1 has been found to reduce apoptosis in other animals and tissues [ 22 – 25 ]. Our previous experiment demonstrated that PGE1 reduces the apoptosis of renal tubular cells in DKD rats [ 25 ]. However, it is unclear whether PGE1 can reduce apoptosis by modulating Bim, and it remains to be investigated whether the JNK/Bim signaling pathway is involved.…”