Carbon monoxide alleviates senescence in diabetic nephropathy by improving autophagy

Area of Science:

• Nephrology
• Cellular Biology
• Molecular Medicine

Background:

• Diabetic nephropathy (DN) involves renal senescence, a state of permanent cell cycle arrest.
• The precise mechanisms driving renal senescence in DN and targeted therapeutic strategies are not fully understood.

Purpose of the Study:

• To investigate the role of CO in regulating renal senescence in DN.
• To elucidate the underlying molecular mechanisms, focusing on the interplay between autophagy and senescence.

Main Methods:

• Diabetic nephropathy (DN) mouse models were established using high-fat diet (HFD) and streptozotocin (STZ).
• In vitro models used high glucose (HG) to induce senescence in renal cells.
• Senescence and autophagy markers were analyzed using qRT-PCR, Western blot, immunofluorescence, and ELISA.
• Autophagy inhibitors and co-immunoprecipitation were employed to clarify CO's mechanism of action.

Main Results:

• Senescence was observed both in vivo and in vitro, and it was reversible by CO.
• CO improved autophagy dysfunction in DN mice by dissociating the Beclin-1-Bcl-2 complex.
• Autophagy inhibition negated the beneficial effects of CO on senescence.
• Autophagy mediated the degradation of senescence-related secretory phenotype (SASP) components, including IL-1β, IL-6, TGF-β, and VEGF.

Conclusions:

• CO demonstrates protective effects against renal senescence and function loss in DN.
• The mechanism involves enhancing autophagy, partly through Beclin-1-Bcl-2 complex dissociation and subsequent SASP degradation.
• These findings offer novel therapeutic avenues for DN and senescence regulation.