Abstract
Tangshen Formula (TSF) is a Chinese Medicine formula that has been reported to alleviate proteinuria and protect renal function in humans and animals with diabetic kidney disease (DKD). However, little is known about its mechanism in improving proteinuria. The dysregulation of podocyte cell-matrix adhesion has been demonstrated to play an important role in the pathogenesis and progression of proteinuric kidney diseases including DKD. In the present study, the underlying protective mechanism of TSF on podocytes was investigated using the murine model of type 2 DKD db/db mice in vivo and advanced glycation end products (AGEs)-stimulated primary mice podocytes in vitro. Results revealed that TSF treatment could significantly mitigate reduction of podocyte numbers and foot process effacement, reduce proteinuria, and protect renal function in db/db mice. There was a significant increase in expression of transient receptor potential canonical channel 6 (TRPC6) and a decrease in expression of talin1 in podocytes of db/db mice. The results of AGEs-stimulated primary mice podocytes showed increased cell migration and actin-cytoskeleton rearrangement. Moreover, primary mice podocytes stimulated by AGEs displayed an increase in TRPC6-dependent Ca2+ influx, a loss of talin1, and translocation of nuclear factor of activated T cell (NFATC) 2. These dysregulations in mice primary podocytes stimulated by AGEs could be significantly attenuated after TSF treatment. 1-Oleoyl-2-acetyl-sn-glycerol (OAG), a TRPC6 agonist, blocked the protective role of TSF on podocyte cell-matrix adherence. In conclusion, TSF could protect podocytes from injury and reduce proteinuria in DKD, which may be mediated by the regulation of the TRPC6/Talin1 pathway in podocytes.
Highlights
Diabetic kidney disease (DKD) is one of the most common and severe complications of diabetes mellitus and is characterized by proteinuria and renal function impairment
The body weights between the mice of db/db group and the mice of db/db + Tangshen Formula (TSF) group were similar at the age of 10 weeks
TSF treatment significantly reduced the body weights of db/db mice compared with the db/db mice without treatment starting from age of 19 weeks till the end of the study
Summary
Diabetic kidney disease (DKD) is one of the most common and severe complications of diabetes mellitus and is characterized by proteinuria and renal function impairment. Changes in podocyte number and/or structure of foot processes have been demonstrated to be the main cause leading to glomerular proteinuria [3]. Numerous studies on podocytes have shown that actin-cytoskeletal disorganization and related protein damage induced by multiple pathogenic factors lead to podocyte injury [4, 5]. Cell-matrix adhesion core structure complexes, including integrins/talins/actin, are crucial for maintaining the podocyte actin cytoskeleton. These adhesion complexes allow podocytes to attach tightly to the glomerular
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