The latest prevention/treatment targets for diabetic nephropathy

The Shang-Zhong Xu group of the Cardiovascular and Metabolic Research Center of the University of Hull in the United Kingdom and the Zeng Bo group of the Institute of Cardiovascular Medicine, Southwest Medical University, China published a titled “ORAI channels are critical for” in “Nature Communications”. “Receptor-mediated endocytosis of albumin” article, using human cell models, biopsies, diabetic mouse models and transgenic mice to prove that ORAI expression silence impairs the reabsorption of albumin by renal epithelial cells and aggravates proteinuria. The discovery of new molecular mechanisms such as related signal pathways related to protein reabsorption provides potential targets for the treatment of diabetic proteinuria.

Diabetic nephropathy (DN) is one of the main causes of end-stage renal disease, and features include proteinuria, glomerular sclerosis, and gradual loss of renal function. More than one-third of diabetic patients suffer from DN. Once they develop end-stage kidney disease, the treatment is often more difficult than other kidney diseases.

The earliest detectable feature of diabetic nephropathy is a slight increase in proteinuria indicators (microalbuminuria), followed by continuous proteinuria causing inflammation and scarring of the renal tubulointerstitium, until the gradual loss of renal function.

Glomerular ultrafiltration and reduced reabsorption of proximal tubules are the two major determinants of proteinuria. Studies have pointed out that in the early stage of DN, affected by proximal tubular epithelial cells (PTECs), the resorption of damaged tubules is a possible cause of the development of proteinuria, but the underlying molecular mechanism is still unknown.

The author of this article compared the calcium ion receptor protein (stromal interaction molecule, STIM) and ORAI calcium channel in kidney tissue sections of healthy people and diabetic patients, and found that ORAI1-3 is preferentially expressed in PTECs, but the expression level of ORAIs in DN patients was significantly down .

Hyperglycemia or insulin signal block can also reduce the expression of ORAI1-3. Using BTP2 and diethylstilbestrol drugs to inhibit ORAI ion channels or silence ORAI protein expression will impair protein uptake.

Transgenic mice expressing a dominant negative mutation of Orai1 (E108Q) (provided by Saiye Bio) showed increased proteinuria. BTP2 was injected into diabetic mice induced by streptozotocin, and proteinuria deteriorated. These evidences indicate that proteinuria is closely related to the expression and activity of ORAIs.

The researchers further observed that with the internalization of ORAI1, the endocytosis of albumin by cells is calcium-dependent. After the calcium ion pool is exhausted, the transmembrane protein Amnionless (AMN) cooperates with ORAIs to form a STIM/ORAI/AMN complex. In the apical membrane of PTECs, STIM1/ORAI1 co-localizes with clathrin, but not caveolin, which proves that the endocytosis is mediated by clathrin.

The etiology and pathogenesis of diabetic nephropathy are unclear, and it is currently believed that there are certain genetic factors. The development of early preventive and therapeutic drugs for proteinuria is of great significance to delay and prevent diabetic nephropathy. This article provides a potential and powerful target for the development of related drugs.