Renalase regulates renal tubular injury in diabetic nephropathy via the p38MAPK signaling pathway

Diabetic nephropathy (DN) is an important complication of diabetes and the leading cause of end-stage renal disease globally. Renal tubular damage occurs to varying degrees in the early stages of DN prior to glomerular damage. Renalase (RNLS) is an amine oxidase, which is produced and secreted by the renal tubular epithelial cells. RNLS is reportedly closely related to renal tubular injury in acute and chronic kidney diseases. Herein, we aimed to evaluate the changes in tubular RNLS expression in DN and its correlation with DN-associated renal tubular injury. Conditional permanent renal tubular epithelial rat-cell line NRK-52E was transfected with pcDNA3-RNLS plasmid or administered recombinant rat RNLS protein and high glucose (HG) dose. A total of 22 adult Sprague-Dawley rats were randomly divided into the control (CON, n = 10) or diabetic nephrology (DN, n = 12) group. Random blood glucose levels of the rats were measured by sampling of the caudal vein weekly. After 8 weeks, the rat's body weight, 24-h urinary albumin concentration, and right kidney were evaluated. Our study suggested the decreased expression levels of RNLS in renal tissue and renal tubular epithelial cells in DN rats, accompanied by renal tubulointerstitial fibrosis, apoptosis of renal tubular epithelial cells, and activation of the p38MAPK signal pathway. Reversing the low RNLS expression can reduce the level of p38MAPK phosphorylation and delay renal tubular injury. Thus, the reduction of renal tubular RNLS expression in DN mediates tubulointerstitial fibrosis and cell apoptosis via the activation of the p38MAPK signal pathway. RNLS plays a key mediating role in DN-associated tubular injury via p38MAPK, which provides new therapeutic targets and a theoretical basis for early prevention and treatment of DN. In vivo, the expressions of fibrosis and apoptosis-related proteins in the renal tubules in the DN group were significantly higher than those of CON group in IHC. TUNEL staining showed the alleviated apoptosis level in the renal tubules, which was accompanied by p38MAPK phosphorylation. In vitro, the increased p-p38MAPK, FN, COL-I, BAX, and cleaved Cas-3 levels associated with the HG-induced low RNLS expression levels were significantly reduced, and BCL-2 was up-regulated after intracellular RNLS overexpression and recombinant rat RNLS treatment in renal tubular epithelial cells.image

Automated summary

Diabetic nephropathy (DN) is a major complication of diabetes and the leading cause of end-stage renal disease worldwide. Renalase (RNLS) is an amine oxidase produced by renal tubular epithelial cells and is closely related to renal tubular injury in kidney diseases. This study evaluated the changes in tubular RNLS expression in DN and its correlation with renal tubular injury.