Nephropathy
Chronic kidney disease (CKD) and acute kidney injury (AKI) are critical components of the cardio-metabolic syndrome and are strongly influenced by obesity, diabetes, and systemic metabolic dysfunction. Our lab investigates both the renal consequences of metabolic disease and the novel concept that the kidney actively contributes to whole-body metabolic homeostasis and inter-organ communication.
We utilize a comprehensive, mechanistic approach to unravel the molecular underpinnings of kidney injury and repair, with a focus on the endocannabinoid system and emerging non-cannabinoid targets. Our research spans across four interrelated domains:
1. Chronic Kidney Disease (CKD) in Obesity and Diabetes
CKD is a major complication of obesity and type 1/2 diabetes, affecting over one-third of patients with these conditions. It is a leading cause of end-stage kidney disease (ESKD) and is closely linked with cardiovascular morbidity and mortality.
We study how peripheral CB1 receptor (CB1R) signaling contributes to diabetic and obesity-induced kidney injury by promoting glomerular and tubular dysfunction, fibrosis, and inflammation. Using mouse models of genetic-, diet-, and STZ-induced diabetes and obesity, we have shown that CB1R antagonism protects against renal injury and improves metabolic parameters in parallel.
2. Acute Kidney Injury (AKI) and Renal Repair
AKI is a sudden and often reversible decline in kidney function, but recovery is frequently incomplete and predisposes patients to CKD. We study both the acute injury phase and the repair/regeneration phase, using a range of clinically relevant AKI models:
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Folic acid-induced AKI (to model crystal nephropathy)
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Ischemia-reperfusion injury (IRI) (to mimic transplant- and surgery-related injury)
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Unilateral ureteral obstruction (UUO) (to study progressive interstitial fibrosis)
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Partial nephrectomy (to mimic surgical loss of renal mass)
We examine how CB1R activation affects tubular injury, mitochondrial dysfunction, and impaired regeneration. We also explore how peripheral CB1R blockade promotes repair and attenuates fibrotic responses.
3. Autosomal Dominant Polycystic Kidney Disease (ADPKD)
ADPKD is the most common genetic kidney disorder, characterized by progressive cyst growth and renal enlargement leading to ESRD. Emerging evidence suggests that altered lipid metabolism and mitochondrial dysfunction contribute to cystogenesis.
We investigate the involvement of CB1R in cyst expansion, cAMP signaling, and metabolic regulation in human and murine ADPKD models. Our aim is to determine the contribution of the ECS to ADPKD development and progression, and whether peripheral CB1R antagonists may slow disease progression and improve renal outcomes.
4. The Kidney as a Metabolic Hub: Inter-Organ Communication
Beyond its excretory function, the kidney plays a central role in systemic energy balance and communicates with other organs to regulate glucose, lipid, and amino acid metabolism. Our lab proposes a novel framework in which the kidney acts as a metabolic "orchestrator" that signals to the liver, adipose tissue, and bone to maintain whole-body homeostasis.
Key Targets and Concepts:
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CB1R: Mediates maladaptive responses in proximal tubules that affect systemic metabolism and bone physiology
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GLUT2: Modulates renal glucose handling and signaling to the liver
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SGLT2: Regulates glycosuria and affects hepatic and adipose tissue responses
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ANT2: Involved in mitochondrial ATP/ADP exchange, influencing energy balance and renal signaling
