The Protective Role of TRPC6 Knockout in the Progression of Diabetic Nephropathy

Abstract

Diabetic nephropathy (DN) is a chronic kidney pathology that leads to end stage renal disease (ESRD). It was previously found that a gain‐of‐function mutation in the Transient Receptor Potential Canonical 6 (TRPC6) channel, a non‐selective cation channel that is highly permeable for calcium ions, causes Focal Segmental Glomerulosclerosis (FSG) that is characterized with podocyte loss. Previous studies from our laboratory indicate that there is an association between the development of DN and over‐activation of the TRPC6 channel. We have demonstrated that there is an increase in TRPC6 expression and activity in the streptozotocin (STZ)‐induced diabetic Dahl Salt‐sensitive (SS) rat, an established model of type 1 DN. We have created the TRPC6 knock‐out on a SS rat background (SSTRPC6−/−), and test the hypothesis that the deletion of TRPC6 will protect podocytes and glomeruli during the development of DN. Four groups of animals – control SS, SSTRPC6−/−, and STZ‐treated SS and SSTRPC6−/− – were utilized in this study. Diabetes development was monitored for 11 weeks after STZ injection with periodic weight, glucose, and urinary output measurements. Glomerular filtration rate (GFR) was measured and tissue collections were made at the end of the protocol. Freshly isolated glomeruli of perfused kidneys were used from all four groups for either electron microscopy or confocal fluorescence microscopy to assess the foot process effacement and basal level of intracellular calcium ([Ca2+]i), respectively. Histochemical analysis of whole kidney slices was done to assess renal injury. There was a decrease in urinary output (49±29 vs 73±39 mL/day/100g BW) and a trend for blunted increase in albuminuria (97±34 vs 112±19 mg/day x 100g BW) in the STZ‐treated SSTRPC6−/− rats compared to the STZ‐SS animals. There was no significant difference in GFR between either of the 4 experimental groups; however there does appear to be a trend for hyperfiltration in the STZ‐treated animals. Importantly, pathological increases in basal [Ca2+]i levels and foot process damage of podocytes during the development of DN was attenuated in the STZ‐treated SSTRPC6−/− animals. Overall, our data indicates that inhibiting the TRPC6 channel may have renoprotective effects and the potential to lead to the development of new pharmacological tools to treat or prevent the progression of DN and kidney damage.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.