Transient Receptor Potential Cation Channel 6 (TRPC6) Contributes to Kidney Injury Induced by Diabetes and Hypertension

Diabetes (DM) and hypertension (HTN) are major risk factors for chronic kidney injury, together accounting for >70% of end-stage renal disease. In this study, we assessed whether DM and HTN interact synergistically to promote kidney dysfunction and if Transient Receptor Potential Cation Channel 6 (TRPC6) contributes to this synergism. In wild type (WT; B6/129s background) and TRPC6 knockout (KO) mice, DM was induced by streptozotocin injection to increase fasting glucose levels to 250-350 mg/dL. HTN was induced by aorta constriction (AC) between the renal arteries. AC increased blood pressure (BP) by ~25 mmHg in the right kidney (above AC) while BP in the left kidney (below AC) returned to near normal after 8 weeks, with both kidneys exposed to the same levels of blood glucose, circulating hormones, and neural influences. Kidneys of WT mice exposed to DM or HTN alone had only mild glomerular injury and urinary albumin excretion. In contrast, kidneys exposed to DM plus HTN (WT-DM+AC mice) for 8 weeks had much greater increases in albumin excretion and histological injury. Marked increased apoptosis was also observed in the right kidneys of WT-DM+AC mice. In contrast, in TRPC6 KO-DM+AC mice, the right kidneys exposed to the same levels of high BP and high glucose had lower albumin excretion, less glomerular damage and apoptotic cell injury compared to right kidneys of WT-DM+AC mice. Our results suggest that TRPC6 may contribute to the interaction of DM and HTN to promote kidney dysfunction and apoptotic cell injury.