Related Experiment Video
Updated: Sep 2, 2025
5/6 Nephrectomy Using Sharp Bipolectomy Via Midline Laparotomy in Rats
Published on: April 4, 2025
Selonsertib Enhances Kidney Protection Beyond Standard of Care in a Hypertensive, Secondary Glomerulosclerosis CKD
Shawn S Badal1, Tareq Al Tuhaifi2, Ya-Fen Yu2,3
1Gilead Sciences, Inc., Foster City, California.
Insights
This study shows that combining selonsertib, an apoptosis signal-regulating kinase 1 (ASK1) inhibitor, with enalapril (an ACE inhibitor) can significantly reduce glomerulosclerosis and kidney function decline in a rat model of chronic kidney disease (CKD).
Area of Science:
- Nephrology
- Pharmacology
- Molecular Biology
Background:
- Chronic kidney disease (CKD) progression remains a significant clinical challenge despite existing therapies.
- Apoptosis signal-regulating kinase 1 (ASK1) plays a key role in glomerulosclerosis and diabetic kidney disease (DKD) progression.
- Selonsertib, a selective ASK1 inhibitor, is under development for DKD treatment.
Purpose of the Study:
- To investigate the additional benefits of selonsertib on established glomerulosclerosis and molecular pathways in a nondiabetic CKD model.
- To evaluate the combination therapy of selonsertib with an angiotensin-converting enzyme inhibitor (ACEI), enalapril.
Main Methods:
- A 5/6 nephrectomy (5/6 Nx) rat model was used to induce CKD.
- Rats with established glomerulosclerosis were randomized into four groups: selonsertib, enalapril, combination therapy, and untreated controls.
- Histologic, biochemical, and molecular analyses were performed to assess kidney function, glomerulosclerosis, apoptosis, and related pathways.
Main Results:
- Combined selonsertib and enalapril treatment significantly reduced glomerulosclerosis, showing greater regression than monotherapy.
- Enalapril reduced systolic blood pressure and albuminuria, while selonsertib preserved kidney function and reduced apoptosis and podocyte loss.
- RNA sequencing indicated that combination therapy modulated pathways involved in extracellular matrix remodeling and wound healing.
Conclusions:
- Selonsertib targets a novel, non-hemodynamic pathway in CKD progression.
- Combining ASK1 inhibition with ACE inhibition offers additive benefits in reducing glomerulosclerosis progression and kidney function decline.
- This combination therapy demonstrates potential for mitigating podocyte loss in CKD.
Background:
Despite widespread use of renin-aldosterone-angiotensin system inhibitors and the benefits of lowering glomerular pressure in patients with CKD, there remains a major unmet need for therapies targeting underlying causes of CKD progression. Apoptosis signal-regulating kinase 1 (ASK1) promotes apoptosis and glomerulosclerosis, and is implicated in the progression of diabetic kidney disease (DKD), a major cause of CKD. Selonsertib is a selective ASK1 inhibitor currently in clinical development for the treatment of DKD. We examined the added benefits of selonsertib on existing glomerulosclerosis and related molecular pathways in the nondiabetic 5/6 nephrectomy (5/6 Nx) rat model in combination with the angiotensin-converting enzyme inhibitor (ACEI) enalapril.
Methods:
Male Sprague Dawley rats underwent 5/6 Nx with kidney biopsy 8 weeks later for assessment of glomerulosclerosis, and were randomized to four treatment groups with equal glomerulosclerosis: selonsertib, enalapril, combination (selonsertib plus enalapril), and untreated controls. Serum creatinine, systolic BP (SBP), and urinary albumin were measured at intervals. Animals were euthanized at week 12 for histologic, biochemical, and molecular analyses.
Results:
All rats developed hypertension, albuminuria, and glomerulosclerosis by week 8. Kidney function further declined, and glomerulosclerosis and albuminuria progressively increased in controls from week 8 to 12. Enalapril treatment alone from week 8 to 12 reduced SBP versus controls, decreased albuminuria, and resulted in numerically lower glomerulosclerosis. Selonsertib alone had no effect on SBP but preserved kidney function. Combined treatment significantly reduced glomerulosclerosis, with more regression than either monotherapy. Enalapril treatment resulted in fewer interstitial macrophages, whereas selonsertib treatment reduced apoptosis and podocyte loss. RNA-seq revealed that combined treatment influenced pathways related to extracellular matrix and wound healing.
Conclusions:
Selonsertib targets a novel, nonhemodynamic pathway in CKD. Our data suggest that ASK1 inhibition, when combined with ACEI, has additive effects to reduce progression of glomerulosclerosis, attenuate kidney function decline, and reduce podocyte loss.
More Related Videos
Related Concept Videos
01:28Antihypertensive Drugs: Potassium-Sparing Diuretics
01:25Antihypertensive Drugs: Direct Renin Inhibitors
01:30Acute Kidney Injury IV: Diagnostic Studies and Prevention
01:26Heart Failure Drugs: Inhibitors of Renin-Angiotensin System
01:28Chronic Kidney Disease III: Interprofessional Care
01:11Renal Failure: Dose Adjustments
Reduced renal clearance and elimination rate are common outcomes of renal impairment. These alterations lead to a prolonged elimination half-life and an altered apparent volume of distribution for drugs. As a result, dosage adjustments are typically necessary to maintain optimal drug levels in the body.
However, dosage adjustments...