A novel combination of exogenous klotho combined with telmisartan ameliorated diabetic cardiomyopathy via an antifibrotic mechanism

Abstract

Diabetic cardiomyopathy (DCM) is a progressive heart disorder associated with diabetes mellitus, leading to structural and functional cardiac abnormalities. The mechanisms responsible include renin-angiotensin-aldosterone (RAAS) activation, inflammation, apoptosis, and metabolic disturbances. Despite well-established epidemiological links, treatments for DCM are elusive. This study evaluated the efficacy of a novel combination of recombinant Klotho (KL) and the angiotensin receptor blocker telmisartan (TEL) in treating DCM, as well as investigating potential mechanisms involved. DCM was induced with a single dose of streptozotocin (55 mg/kg, i.p.), followed by a 4-week induction period. For treatment, rats were assigned to five groups: Normal control (NC), Diabetic control (DC), DC + KL (0.01 mg/kg, S.C.), DC + TEL (10 mg/kg, p.o.), and KL + TEL combination. Plasma biochemistry assessed cardiac damage (LDH, CK-MB) and stress markers (ANP, BNP). Electrocardiogram (ECG) measured heart parameters, including heart rate (HR), QTc, JT interval, RR interval, and Tpeak–Tend intervals. Histological analysis (H&E, Masson's trichrome, and Picrosirius red) was performed to assess myocardial structure and fibrosis. Lastly, immunohistochemistry analysis was performed to check the expression of transforming growth factor-β1 (TGF-β1), pSMAD 2/3, matrix metalloproteinase 9 (MMP9), and PRKN. KL and TEL combination treatment significantly reduced cardiac damage markers, reduced ECG abnormalities, including QTc, improved HR while suppressing pro-fibrotic signaling, enhancing mitophagy, and decreasing fibroblast proliferation. The involvement of pathways involving TGF-β1, pSMAD-2/3, MMP9, and pFOXO3a conferred protection to the heart in experimental in-vivo settings. These findings suggest that the combination of KL and TEL effectively mitigates key pathological features of DCM, highlighting its potential as a targeted treatment strategy.