Abstract: PO1975
The Role of Opioid Receptor Signaling in Podocytes and Renal Damage in Dahl Salt-Sensitive Rats
Session Information
- Podocyte Biology
October 22, 2020 | Location: On-Demand
Abstract Time: 10:00 AM - 12:00 PM
Category: Glomerular Diseases
- 1204 Podocyte Biology
Authors
- Golosova, Daria, Medical College of Wisconsin Department of Physiology, Milwaukee, Wisconsin, United States
- Palygin, Oleg, Medical College of Wisconsin Department of Physiology, Milwaukee, Wisconsin, United States
- Levchenko, Vladislav, Medical College of Wisconsin Department of Physiology, Milwaukee, Wisconsin, United States
- Klemens, Christine Anne, Medical College of Wisconsin Department of Physiology, Milwaukee, Wisconsin, United States
- El-Meanawy, Ashraf, Medical College of Wisconsin Department of Medicine, Milwaukee, Wisconsin, United States
- Staruschenko, Alexander, Medical College of Wisconsin Department of Physiology, Milwaukee, Wisconsin, United States
Background
The rise in opioid use underscores the urgent need to better understand the direct and indirect effects of opioids on renal function, especially in patients with chronic kidney disease (CKD) or hypertension. The extensive use of opioids is strongly correlated with poor cardiovascular outcomes. We hypothesize that stimulation of opioid receptors (ORs) elevates intracellular calcium level in podocytes leading to kidney damage and progression of hypertension.
Methods
Freshly isolated glomeruli from Dahl salt-sensitive (SS) rats, human kidneys and immortalized human podocytes were used to elucidate the contribution of specific ORs to podocyte calcium flux. Calcium response in the podocytes was analyzed via ratiometric confocal fluorescent microscopy. For chronic studies Dahl SS rats were on a 0.4% (LS) or 8% (HS) NaCl diets for 14 days with or without a daily intravenous bolus infusion of BRL52537, a potent and selective kappa-OR agonist.
Results
Stimulation of kappa-ORs, but not mu-ORs or delta-ORs, mediated calcium influx in podocytes through activation of TRPC6 channels in rat and human kidney. The effect of BRL52537 was completely abolished when we used the 0 mM calcium media or when SAR7334 (a TRPC6 channel inhibitor) was applied. Triggering the kappa-OR/TRPC6 pathway induced podocyte cell shape changes via actin cytoskeleton remodeling. In vivo studies revealed that SS rats chronically treated with BRL52537 exhibited augmented blood pressure (MAP was 179 ± 15 mmHg vs. 151 ± 11 mmHg), nephrinuria, albuminuria, and elevation in podocyte calcium in BRL52537 treated Dahl SS rats.
Conclusion
Stimulation of kappa-OR modulates calcium influx in podocyte via TRPC6 channels. The opiate-induced increase in the calcium flux in podocytes is expected to contribute to podocytopathy, proteinuria, kidney injury and progression of salt-induced hypertension. These findings are important to advance our knowledge of the pathogenesis of the development of CKD and hypertension in the context of pain management.
Funding
- Other NIH Support