Mineralocorticoid Receptor Blocker Protects against Podocyte-Dependent Glomerulosclerosis

Abstract

Background: We previously showed that angiotensin type 1 receptor (AT1) blocker (ARB) attenuates glomerular injury in Nphs1-hCD25 (NEP25) transgenic mice, a model of selective podocyte injury. However, subsequent studies in NEP25 mice with podocyte-specific deficiency of AT1 revealed that the protective effects of ARB are not through the podocyte AT1, thereby raising the possibility that the protective effects of ARB involve mineralocorticoids.

Methods: NEP25 mice were treated with the mineralocorticoid receptor blocker (MRB) spironolactone (25 mg/kg/day, n = 10), the ARB losartan (250 mg/kg/day, n = 11), both (ARB+MRB, n = 8) or vehicle (Vehicle, n = 9) from day -7 to day 9 of induction of podocyte injury.

Results: ALTHOUGH MRB DID NOT REDUCE SYSTOLIC BLOOD PRESSURE OR PROTEINURIA, ADDITION OF MRB TO ARB SIGNIFICANTLY ATTENUATED GLOMERULOSCLEROSIS (GLOMERULOSCLEROSIS INDEX: ARB+MRB 1.67 ± 0.19 vs. MRB 2.01 ± 0.29, ARB 2.35 ± 0.19, and Vehicle 2.25 ± 0.26, p < 0.05) and preserved the number of WT1-positive podocytes (ARB+MRB 152.5 ± 9.7 vs. MRB 117.2 ± 9.0 or ARB 113.6 ± 7.4, and ARB+MRB vs. Vehicle 97.5 ± 4.0 per glomerulus; p < 0.05).

Conclusion: These data suggest that, while MRB does not attenuate proteinuria caused by podocyte-specific injury, it provides protective effects against glomerulosclerosis that is independent of systemic blood pressure.

Keywords: Aldosterone; Angiotensin II; Blood pressure; Glomerulosclerosis; NEP25; Podocyte; Proteinuria; Receptor.

Fig. 1

SGK1 staining in NEP25 mice treated with ARB, MRB or both. NEP25 mice from the Vehicle group showed SGK1-positive staining in both tubular epithelial cells and glomeruli, while there were only a few positivities in the ARB, MRB and ARB+MRB groups, suggesting the effects of ARB and/or MRB.

Fig. 2

Histology of NEP25 mice treated with ARB, MRB or both. NEP25 mouse, a model of specific podocyte damage, showed extensive glomerulosclerosis, an increased area positive for collagen IV (Col IV) and a decreased number of WT1-positive podocytes in the glomerulus. Treatment with the ARB losartan, the MRB spironolactone, or with both in combination attenuated podocyte damage-induced glomerulosclerosis, collagen deposition and podocyte loss.