Diabetes mellitus (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 whether
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), whereas BP in the left kidney (below AC) returned to near normal after 8 wk, 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, WT kidneys exposed to DM plus HTN (WT-
DM + AC mice) for 8 wk 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 mice with
DM + AC, right kidneys exposed to the same levels of high BP and high
glucose had lower
albumin excretion and less glomerular damage and apoptotic cell injury compared with 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.NEW & NOTEWORTHY A major new finding of this study is that the combination of moderate diabetes and
hypertension promoted marked renal dysfunction,
albuminuria, and apoptotic cell injury, and that these effects were greatly ameliorated by
transient receptor potential cation channel 6 deficiency. These results suggest that
transient receptor potential cation channel 6 may play an important role in contributing to the interaction of diabetes and
hypertension to promote kidney injury.