Protease-Activated Receptor 1–Mediated Damage of Podocytes in Diabetic Nephropathy

Author:

Bohovyk Ruslan1,Khedr Sherif2,Levchenko Vladislav1,Stefanenko Mariia3,Semenikhina Marharyta3,Kravtsova Olha1,Isaeva Elena4,Geurts Aron M.4,Klemens Christine A.15,Palygin Oleg36,Staruschenko Alexander157ORCID

Affiliation:

1. 1Department of Molecular Pharmacology and Physiology, University of South Florida, Tampa, FL

2. 2Department of Physiology, Faculty of Medicine, Ain-Shams University, Cairo, Egypt

3. 3Department of Medicine, Division of Nephrology, Medical University of South Carolina, Charleston, SC

4. 4Department of Physiology, Medical College of Wisconsin, Milwaukee, WI

5. 5Hypertension and Kidney Research Center, University of South Florida, Tampa, FL

6. 6Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC

7. 7James A. Haley Veterans’ Hospital, Tampa, FL

Abstract

There is clinical evidence that increased urinary serine proteases are associated with the disease severity in the setting of diabetic nephropathy (DN). Elevation of serine proteases may mediate [Ca2+]i dynamics in podocytes through the protease-activated receptors (PARs) pathway, including associated activation of nonspecific cation channels. Cultured human podocytes and freshly isolated glomeruli were used for fluorescence and immunohistochemistry stainings, calcium imaging, Western blot analysis, scanning ion conductance microscopy, and patch clamp analysis. Goto-Kakizaki, Wistar, type 2 DN (T2DN), and a novel PAR1 knockout on T2DN rat background rats were used to test the importance of PAR1-mediated signaling in DN settings. We found that PAR1 activation increases [Ca2+]i via TRPC6 channels. Both human cultured podocytes exposed to high glucose and podocytes from freshly isolated glomeruli of T2DN rats had increased PAR1-mediated [Ca2+]i compared with controls. Imaging experiments revealed that PAR1 activation plays a role in podocyte morphological changes. T2DN rats exhibited a significantly higher response to thrombin and urokinase. Moreover, the plasma concentration of thrombin in T2DN rats was significantly elevated compared with Wistar rats. T2DNPar1−/− rats were embryonically lethal. T2DNPar1+/− rats had a significant decrease in glomerular damage associated with DN lesions. Overall, these data provide evidence that, during the development of DN, elevated levels of serine proteases promote an excessive [Ca2+]i influx in podocytes through PAR1-TRPC6 signaling, ultimately leading to podocyte apoptosis, the development of albuminuria, and glomeruli damage. Article Highlights Increased urinary serine proteases are associated with diabetic nephropathy. During the development of diabetic nephropathy in type 2 diabetes, the elevation of serine proteases could overstimulate protease-activated receptor 1 (PAR1). PAR1 signaling is involved in the development of DN via TRPC6-mediated intracellular calcium signaling. This study provides fundamental knowledge that can be used to develop efficient therapeutic approaches targeting serine proteases or corresponding PAR pathways to prevent or slow the progression of diabetes-associated kidney diseases.

Funder

National Institutes of Health

Department of Veteran Affairs

SC SmartState Centers of Excellence

American Physiological Society

Publisher

American Diabetes Association

Subject

Endocrinology, Diabetes and Metabolism,Internal Medicine

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