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Activating soluble guanylyl cyclase attenuates ischemic kidney damage
Falk-Bach Lichtenberger1, Minze Xu1, Cem Erdoğan1
1Institute of Translational Physiology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.
Kidney International
|November 21, 2024
Summary
Directly activating soluble guanylyl cyclase (sGC) with BAY 60-2770 protected kidneys from acute injury and the transition to chronic kidney disease by improving blood flow and reducing damage.
Area of Science:
- Nephrology
- Cardiovascular Research
- Pharmacology
Background:
- Acute kidney injury (AKI) can progress to chronic kidney disease (CKD), characterized by microvascular damage, inflammation, and fibrosis.
- Current treatments for AKI lack specific protective mechanisms against the transition to CKD.
- Soluble guanylyl cyclase (sGC) activators offer a potential therapeutic strategy independent of nitric oxide.
Purpose of the Study:
- To investigate the kidney-protective effects of a novel sGC activator, BAY 60-2770.
- To evaluate the impact of sGC activation on kidney microvasculature, blood flow, fibrosis, and inflammation in an AKI model.
- To determine if sGC activation can attenuate the progression from AKI to CKD.
Main Methods:
- A rat model of unilateral ischemia reperfusion injury (IRI) was used to induce AKI.
- Animals received either vehicle or the sGC activator BAY 60-2770 post-IRI.
- Kidney function, histology, gene expression, and microvascular parameters were assessed at various time points (days 3, 7, 14, and 84).
- In vitro studies using human tubular cells (HK-2) exposed to hypoxia or TGF-β were also conducted.
Main Results:
- Vehicle-treated rats exhibited microvascular narrowing, inflammation, fibrosis, and elevated kidney injury markers.
- BAY 60-2770 treatment increased tissue cGMP, dilated kidney microvasculature, and improved renal blood flow and oxygenation.
- sGC activator treatment significantly reduced kidney weight loss, cell damage, fibrosis, inflammation, and improved plasma creatinine and cystatin C levels.
- In vitro, BAY 60-2770 modulated gene expression patterns in tubular cells under stress.
Conclusions:
- Direct sGC activation with BAY 60-2770 demonstrates significant kidney-protective effects in an AKI model.
- This intervention attenuates the progression from AKI to CKD by preserving microvasculature and reducing pathological changes.
- sGC activation represents a promising therapeutic approach for preventing kidney disease progression.
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