Uromodulin aggravates renal tubulointerstitial injury through activation of the complement pathway in rats

Abstract

Uromodulin (Umod) is the most abundant constituent of urine in humans and exclusively found in the kidney tubular epithelium. However, the specific role of Umod in renal tubulointerstitial injury is yet to be understood. The present study was conducted with aim of investigating the potential therapeutic mechanism of Umod in the regulation of renal tubulointerstitial injury. Protein expression of Umod in renal tubular epithelial cells was measured with the conduction of Western blot analysis. Enzyme‐linked immunosorbent assay and immunofluorescence assay were performed to detect the complement activation products and the activation products of surface deposition. The expression of C1q, C2, C4, B factor, C3, C5, H factor, CD46, CD55, C3aR, and C5aR were determined with the use of reverse‐transcription quantitative polymerase chain reaction and Western blot analyses. Subsequently, the unilateral ureteral obstruction (UUO) rat model was established. Renal tubulointerstitial injury was assessed with the application of hematoxylin–eosin staining and Masson staining in rats. UUO rats and normal rats were injected with si‐NC or si‐Umod and complement inhibitor. UUO rats were observed to have serious impairment of kidney tubule, renal tubular dilation, and epithelial atrophy, with downregulated Umod and activated complement pathway. Silencing of Umod resulted in the activation of complement system while promoting interstitial fibrosis in renal tubules. Moreover, addition of complement inhibitor significantly alleviated the renal tubule injury and fibrosis. Collectively, our study suggests that silencing of Umod mediates the complement pathway, exacerbating renal tubulointerstitial injury in rats, which provides insight into the development of novel therapeutic agents for renal tubulointerstitial injury.

The Reduction of Uromodulin, Complement Factor H, and Their Interaction Is Associated with Acute Kidney Injury to Chronic Kidney Disease Transition in a Four-Time Cisplatin-Injected Rat Model

“…Many proteins are produced or decreased in response to nephrotoxicity. Uromodulin (also known as Tamm–Horsfall protein), is a mucoprotein primarily synthesized by the thick ascending limb (TAL) of the loop of Henle [ 10 ], and is associated with improved tubular function in the general population and lower risk of AKI [ 11 , 12 , 13 ] and CKD [ 14 ]. Uromodulin knockout mice developed more aggressive renal damage in an ischemia/reperfusion injury (IRI) model than wild type mice [ 12 , 13 ].…”

“…The complement alternative pathway (AP) was shown to trigger most of the complement activation in AKI, and selective inhibitors of AP protected the tubular cells [ 19 , 20 ]. Complement factor H (CFH), as a major regulatory component of AP, is reported to decrease during AKI [ 14 , 19 ]. Nevertheless, the detailed protection mechanism of CFH in kidney damage needs to be explored to accelerate relevant drug development.…”

Uromodulin as a potential candidate marker for predicting the course of chronic kidney disease

“…Захват внутрішньоклітинного уромодуліну всередині ER, імовірно, відіграє важливу роль у визначенні тубулоінтерстиціального фіброзу та ниркової недостатності [19,47].…”