Abstract Body: Background:
Acute kidney injury (AKI) is known to be associated with adverse effects in remote organs. AKI increases the risk of cardiovascular death by 86%, myocardial infarction (MI) by 40%, and stroke by 15%. AKI also worsens pre-existing cardiac conditions and procedures, such as heart failure, MI, cardiac surgery and percutaneous coronary interventions. However, the mechanisms and mediators of detrimental kidney-heart crosstalk remain largely unknown. In our previous work, we showed that circulating osteopontin (OPN/Spp1) released by the AKI kidney drives remote lung inflammation and hypoxemia (Khamissi Sci Adv 2022, Komaru JCI 2025).

Methods:
To study AKI induced cardiac dysfunction, we used C57BL/6 (wt) and OPN-KI (OPN-R¹⁵³A) knock-in mice, carrying a point mutation in OPN rendering it uncleavable by thrombin. We implanted Angiotensin II/ Phenylephrine (AngII/PE) osmotic minipumps in sham or AKI (unilateral renal ischemia reperfusion injury) wt or OPN-KI mice on day 7 after surgery to induce hypertensive cardiac injury. On days 14 and 28, we examined mice for early inflammation and cardiac remodeling, respectively. Blood pressure measurements were performed using an intravascular pressure probe. Masson’s trichome and H&E stainings were performed on paraffin sectioned hearts and kidneys to measure cardiac fibrosis and tubular injury, respectively.

Result:
We found that wt and OPN-KI mice showed low to mildly elevated serum BUN on Day 1+14+28 (20-40 mg/dl). Kidney H&E staining from both groups showed equal levels of significant kidney fibrosis. Wt but not OPN-KI mice showed equal blood pressure elevations. Yet, only Wt but not OPN-KI mice showed increased cardiac macrophages and increased cardiac injury markers on Day 14 and increased perivascular fibrosis on Day 28; interstitial fibrosis was not different between groups.

Conclusion:
Our data suggests that OPN has an important role in driving AKI-induced cardiac dysfunction and may be exploited therapeutically to reduce morbidity and mortality in kidney and cardiovascular disease.