Role of metallothionein 3 in diabetic nephropathy via interplay with HIF-1α.

UNLABELLED

Metallothioneins (MTs) are a cysteine-rich protein that scavenges reactive oxygen species. Hypoxia is involved in the progression of diabetic nephropathy (DN) and aggravates oxidative stress. Hypoxia dramatically induced , whereas induced around twofold increment in , but inhibited in human renal proximal tubular epithelial cells (HRPTECs). Given that the role of MT3 in DN remains unclear, we explored the involvement of MT3 in DN. Microarray analysis also identified MT3-regulated candidate genes, including ceruloplasmin () and cytochrome b reductase 1 (), as well as FGF-Klotho (KL)-FGFR complexes in HRPTECs. Hypoxia significantly induced expression through HIF-1-dependent mechanisms, and MT3 small interfering RNA (siRNA) decreased , , and expression under hypoxic conditions. In humanized MT3-BACTg mice, except HIF-1α, diabetes significantly increased the expression of MT3, CP, CYRBD1, FGFR2, and KL in the renal cortex in MT3-BACTg mice. Diabetic MT3-BACTg mice presented more severely damaged mitochondria in proximal tubules than their wild-type littermates did, accompanied with peritubular capillary obstruction by swollen endothelial cells. Moreover, the proximal tubules-specific overexpression of MT3 in mice (MT3Tg) represented no overlap in the protein expression between MT3 and HIF-1α in diabetic kidney. Accordingly MT3 siRNA significantly augmented HIF-1α protein and in HRPTECs. Finally, expression in the renal tubulointerstitium was positively correlated with the glomerular filtration rate (GFR) in DN subjects by data from Nephroseq. In conclusion, these results showed that there might be a unique interplay between MT3 and HIF-1α in diabetic kidney of to regulate hypoxia-induced HIF-1α expression.

SUPPLEMENTARY INFORMATION

The online version contains supplementary material available at 10.1007/s13340-025-00840-y.