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Am J Physiol Renal Physiol (August 15, 2007). doi:10.1152/ajprenal.00185.2007
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Submitted on April 17, 2007
Accepted on August 9, 2007

Downregulation of TRPC6 protein expression by high glucose, a possible mechanism for the impaired Ca2+ signaling in glomerular mesangial cells in diabetes

Sarabeth Graham1, Min Ding1, Sherry Sours-Brothers1, Thomas Yorio2, Jian-xing Ma3, and Rong Ma4*

1 Integrative Physiology, University of North Texas Health Science Center, Fort Worth, Texas, United States
2 Pharmacology & Neuroscience, University of North Texas Health Science Center, Fort Worth, Texas, United States
3 Cell Biology, Medicine, Univ. of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States
4 Integrative Physiology, University of North Texas Health Science Center, Fort Worth, Texas, United States; Physiology, Anhui Medical University, Hefei, Anhui, China

* To whom correspondence should be addressed. E-mail: rma{at}hsc.unt.edu.

The present study was performed to investigate whether TRPC6 participated in Ca2+ signaling of glomerular mesangial cells (MCs) and expression of this protein was altered in diabetes. Western blots and real-time PCR were used to evaluate the expression level of TRPC6 protein and mRNA, respectively. Cell-attached patch clamp and fura-2 fluorescence measurements were utilized to assess angiotensin II (Ang II)-stimulated membrane currents and Ca2+ responses in MCs. In cultured human MCs, high glucose significantly reduced expression of TRPC6 protein, but there was no effect on either TRPC1 or TRPC3. The high glucose-induced effect on TRPC6 was time and dose dependent with the maximum effect observed on day 7 and at 30 mM glucose, respectively. In glomeruli isolated from streptozotocin-induced diabetic rats, TRPC6, but not TRPC1, was markedly reduced compared to the glomeruli of control rats. Furthermore, TRPC6 mRNA in MCs was also significantly decreased by high glucose as early as one day after treatment with maximal reduction on day 4. Patch clamp experiments showed that Ang II-stimulated membrane currents in MCs were significantly attenuated or enhanced by knockdown or overexpression of TRPC6, respectively. Fura-2 fluorescence measurements revealed that the Ang II-induced Ca2+ influxes were markedly inhibited in MCs with TRPC6 knockdown, reminiscent of the impaired Ca2+ entry in response to Ang II in high glucose-treated MCs. These results suggest that the TRPC6 protein expression in MCs was downregulated by high glucose and the deficiency of TRPC6 protein might contribute to the impaired Ca2+ signaling of MCs seen in diabetes.




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