The Inhibitory Effect of Eplerenone on Cell Proliferation in the Contralateral Kidneys of Rats with Unilateral Ureteral Obstruction

Abstract

Background: The unilateral ureteral obstruction (UUO) model not only induces renal interstitial fibrosis in the obstructed kidney but also induces injury in the contralateral kidney. We hypothesized that activation of the mineralocorticoid receptor (MR) may induce fibrosis in the early stage of UUO. Methods: Thirty male Sprague-Dawley rats weighting 200 ± 10 g were used in this study and randomly divided into 3 groups: a UUO group, a UUO and eplerenone group, and a sham group. The contralateral kidney and plasma were harvested for further study 10 days after surgery. Results: The level of plasma aldosterone (869.95 ± 55.851 pg/mL) was significantly higher in the UUO group than that in the sham group (478.581 ± 36.186 pg/mL vs. UUO, p < 0.05). The infiltrated inflammatory cells (F4/80) and deposited collagens were increased significantly in the contralateral kidneys in the UUO group compared to those in the sham group, which were decreased by eplerenone. However, proliferating cell nuclear antigen was increased 2.47 times in the UUO group compared to the sham group in the contralateral kidney (p < 0.01), and those changes are attenuated by eplerenone. The expression of SGK-1 protein and mRNA was upregulated in the contralateral kidney in the UUO group, which is suppressed by eplerenone treatment. NF-κB pathway effecters were also changed markedly in the contralateral kidney in the UUO group and partly reversed by eplerenone. Conclusion: Aldosterone induces inflammatory cell proliferation via the MR/SGK-1 and NF-κB pathways and eventually leads to fibrosis in the contralateral kidney.

Eplerenone Ameliorates Cell Pyroptosis in Contralateral Kidneys of Rats with Unilateral Ureteral Obstruction

“…Renal failure induced by obstructive nephropathy is related to contralateral kidney injury [5]. In this study, we first confirmed cell pyroptosis in the contralateral kidney in UUO rats, which was induced by MR activation.…”

“…Our previous study has already indicated that plasma Ald concentrations were elevated in the UUO animals [5]. To confirm this in the current study and further investigated whether MR activation results in inflammatory activation of NLRP3 inflammasome, we examined the expression of serum and glucocorticoid-inducible protein kinase-1 (SGK-1) and nuclear factor kappa B (NF-κB) using western blot.…”

“…All the animals were euthanized 10 days after UUO or sham surgeries. Meanwhile, the contralateral kidneys were collected and used for study (the protocol was the same as previously used one [5]). …”

“…It affects both the obstructed and contralateral kidneys. Some patients continue to experience progression of renal damage or failure even after obstruction has been relieved [1][2][3], indicating injuries in the contralateral kidney [4,5]. Our previous research indicated that cell proliferation took part in the contralateral kidney damage [5].…”

“…Several clinical studies implied a relationship between high plasma Ald levels and renal deterioration [10][11][12]. Elevated plasma Ald concentrations were found in UUO animals [5,13] that may activate NLRP3 inflammasomes [14,15]. However, it remains to be discovered whether Ald participates in contralateral kidney injury by activating NLRP3 inflammasomes, resulting in cell pyroptosis post UUO.…”