RAGE-aptamer attenuates deoxycorticosterone acetate/salt-induced renal injury in mice

Area of Science:

• Nephrology
• Molecular Biology
• Pharmacology

Background:

• Mineralocorticoid receptor (MR) signaling contributes to hypertensive renal injury.
• Advanced glycation end products (AGE) interacting with their receptor (RAGE) drive renal disease progression.
• The pathological crosstalk between the AGE-RAGE axis and the MR system in kidney disease is not well understood.

Purpose of the Study:

• To investigate the pathological crosstalk between the AGE-RAGE axis and the MR system in kidney disease.
• To evaluate the therapeutic potential of a RAGE-targeting aptamer (RAGE-apt) in a mouse model of hypertensive renal injury.

Main Methods:

• Screening of a DNA aptamer targeting RAGE (RAGE-apt) in vitro.
• Administration of RAGE-apt to uninephrectomized deoxycorticosterone acetate (DOCA)/salt-induced hypertensive mice.
• Assessment of renal injury markers, including mesangial matrix expansion, tubulointerstitial fibrosis, oxidative stress, and urinary albumin excretion (UAE).
• Co-localization studies of RAGE, Rac1, and MR in podocytes.
• In vitro experiments using murine podocytes treated with aldosterone (Aldo) and carboxymethyllysine (CML).

Main Results:

• RAGE, Rac1, and MR were co-localized in podocytes of DOCA mice.
• RAGE deletion significantly reduced kidney damage markers (fibrosis, oxidative stress, UAE) in DOCA mice.
• RAGE-apt treatment attenuated increases in CML, RAGE, nitrotyrosine, Rac1, and MR levels, and reduced UAE in DOCA mice.
• Aldosterone stimulated RAGE expression, while CML increased MR and Rac1 levels in podocytes, effects blocked by RAGE-apt.

Conclusions:

• There is a significant crosstalk between the AGE-RAGE axis and the aldosterone-MR system in kidney disease.
• RAGE-apt effectively ameliorates hypertensive renal injury in a preclinical model.
• RAGE-apt represents a potential novel therapeutic strategy for MR-associated renal diseases.