TRPC6-Calpain-1 Axis Promotes Tubulointerstitial Inflammation by Inhibiting Mitophagy in Diabetic Kidney Disease

Introduction: Renal tubulointerstitial inflammation represents an effective indicator for predicting the progression of diabetic kidney disease (DKD). Mitophagy abnormality is 1 of the most important factors involved in tubule injury. However, the exact molecular mechanism underlying mitophagy abnormality-mediated tubulointerstitial inflammation in DKD remains poorly understood.

Methods: In this study, a streptozotocin-induced DKD mouse model was established and HK-2 cells treated with high glucose (HG) served as an in vitro model. Tubular mitophagy was regulated through pharmacological urolithin A (UA) administration. The functional effect of the transient receptor potential cation channel, subfamily C, member 6 (TRPC6) was explored using genetic interventions in vivo and in vitro.

Results: We found that renal tubulointerstitial inflammation in DKD was closely associated with mitophagy inhibition, which was mediated by disturbance of PINK1/Parkin pathway. Mitophagy activation significantly attenuated tubular injury and tubulointerstitial inflammation. Further, it was found that TRPC6 was markedly increased in DKD and played an essential role in mitophagy inhibition by activating calpain-1. Knockdown of Trpc6 partially reversed mitophagy abnormality and consequently attenuated tubular injury and tubulointerstitial inflammation in vivo and in vitro. Finally, we found that tubular TRPC6-mediated mitophagy inhibition was blocked with BAPTA (a specific Ca²⁺ chelator) or calpeptin (a specific calpain-1 inhibitor).

Conclusion: Our study reveals that TRPC6-calpain-1 axis promotes tubulointerstitial inflammation in DKD by inhibiting mitophagy.