Transient receptor potential cation channel 6 contributes to kidney injury induced by diabetes and hypertension

Abstract

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.

Analysis of potential biomarkers for diabetic kidney disease based on single-cell RNA-sequencing integrated with a single-cell sequencing assay for transposase-accessible chromatin

“…Under DKD conditions, signaling pathways such as PPAR, TGF-β, MAPK, and NLRP3 are activated in the renal tubules, and they transition from adaptive to pathological changes. We observed that klf10 and klf11 , which encode factors involved in the TGF-β signaling pathway [ 21 ] and inhibit cell growth, regulating extracellular matrix, and inducing cell apoptosis [ 22 , 23 ] are significantly upregulated in the proximal tubules. Consistently, the cell numbers in the PTS3 and PTS2 clusters were significantly lower in db/db mice than in db/m mice, this could be attributed to increased Klf10 and Klf11 expression.…”

Genome-wide meta-analysis identifies novel maternal risk variants and enables polygenic prediction of preeclampsia and gestational hypertension

“…Along with other newly identified HDP-associated loci ( TNS2 55 and PLCE1 29 ), TRPC6 has also been linked to glomerular function. It has been implicated in focal segmental glomerulosclerosis and diabetic nephropathy 56 and mediates the proteinuria and renal dysfunction induced by exposure to hypertension and diabetes 57 . In addition, the progesterone receptor mediates the physiologic response to progesterone, including pregnancy-associated vasodilation 58 .…”

Transient Receptor Potential Canonical 6 (TRPC6) Channel in the Pathogenesis of Diseases: A Jack of Many Trades

“…It was demonstrated that TRPC6 may function in conjugation with Protease-Activated Receptors (PARs) and GPCRs, contributing towards the development of glomerular injury and kidney disease in the patients presenting with diabetes. Notably, Wang et al found that the simultaneous induction of hypertension and streptozotocin-induced moderate diabetes in the same animal leads to markedly increased albuminuria and kidney injury compared to the conditions when hypertension and diabetes were induced separately, with genetic ablation of TRPC6 significantly reducing albuminuria and kidney injury [ 25 ]. Consistently, Spires et al also found that TRPC6 plays an important role in the development of DKD [ 26 ].…”