Regulation and Dysregulation of TRPC6 Channels in Podocytes

Date

2019-12

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Abstract

Chronic kidney disease (CKD) that is characterized by the gradual loss of renal function over time is the leading cause of renal failure and end-stage renal disease (ESRD) among Americans. In the present dissertation, we study two of the most common CKDs: Diabetic Nephropathy (DN) and Focal Segmental Glomerulosclerosis (FSGS). Many studies have been dedicated to determine the mechanisms implicated in the pathophysiology of these diseases. However, there is an unmet need for new therapeutic strategies that requires a better understanding of these mechanisms and pathways contributing to disease development and progression. First, we determine the effects of inactivation of canonical transient receptor potential-6 (TRPC6) channel in DN. TRPC6 is a nonselective Ca2+-permeable cation channel and its dysregulation has been implicated in pathophysiology of glomerular diseases. DN is induced by STZ injection in Trpc6del/del and Trpc6wt/wt Sprague-Dawley rats. Although we had previously reported a protective effect of TRPC6 inactivation in our other disease models including the chronic puromycin aminonucleoside (PAN) nephrosis model of acquired FSGS, here we did not see any protection against STZ-induced DN in our animals. Next, we focus on the mechanisms and pathways by which serum soluble urokinase-type plasminogen activator receptor (suPAR) modulates TRPC6 channels in podocytes. Podocytes are highly specialized cells on the surface of glomeruli in kidney and podocyte injury is the main contributing factor in development of glomerular diseases. suPAR is a circulating glomerular permeability factor implicated in primary and recurrent FSGS as well as in DN. We show that suPAR activates β3-integrin in podocytes and cause an increase in cytosolic reactive oxygen species (ROS). suPAR effects lead to increase in membrane trafficking and activation of TRPC6 channels in podocytes. Lastly, we study the effects of insulin-like growth factor-1 (IGF-1) on podocytes. IGF-1 is a peptide hormone with structural similarities to insulin that increase glomerular filtration rate (GFR) and induce compensatory renal growth. We show that IGF-1 upregulates TRPC6 channels in podocytes through generation of ROS and activation of Src family protein kinases. In addition, IGF-1 appears to trigger podocyte hypertrophy in vitro. These results suggest that TRPC6 is a potential therapeutic target for treatment of FSGS but not DN.

Description

Keywords

TRPC6, Podocytes, Chronic kidney diseases

Citation

Portions of this document appear in: Khayyat, Naghmeh Hassanzadeh, Eun Young Kim, and Stuart E. Dryer. "TRPC6 inactivation does not protect against diabetic kidney disease in streptozotocin (STZ)‐treated Sprague‐Dawley rats." FASEB BioAdvances (2019). And in: Kim, Eun Young, Naghmeh Hassanzadeh Khayyat, and Stuart E. Dryer. "Mechanisms underlying modulation of podocyte TRPC6 channels by suPAR: role of NADPH oxidases and Src family tyrosine kinases." Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease 1864, no. 10 (2018): 3527-3536.