Endoglin Is an Important Mediator in the Final Common Pathway of Chronic Kidney Disease to End-Stage Renal Disease

Abstract

Chronic kidney disease (CKD) is a slow-developing, progressive deterioration of renal function. The final common pathway in the pathophysiology of CKD involves glomerular sclerosis, tubular atrophy and interstitial fibrosis. Transforming growth factor-beta (TGF-β) stimulates the differentiation of fibroblasts towards myofibroblasts and the production of extracellular matrix (ECM) molecules, and thereby interstitial fibrosis. It has been shown that endoglin (ENG, CD105), primarily expressed in endothelial cells and fibroblasts, can function as a co-receptor of TGF signaling. In several human organs, endoglin tends to be upregulated when chronic damage and fibrosis is present. We hypothesize that endoglin is upregulated in renal interstitial fibrosis and plays a role in the progression of CKD. We first measured renal endoglin expression in biopsy samples obtained from patients with different types of CKD, i.e., IgA nephropathy, focal segmental glomerulosclerosis (FSGS), diabetic nephropathy (DN) and patients with chronic allograft dysfunction (CAD). We showed that endoglin is upregulated in CAD patients (p < 0.001) and patients with DN (p < 0.05), compared to control kidneys. Furthermore, the amount of interstitial endoglin expression correlated with eGFR (p < 0.001) and the amount of interstitial fibrosis (p < 0.001), independent of the diagnosis of the biopsies. Finally, we investigated in vitro the effect of endoglin overexpression in TGF-β stimulated human kidney fibroblasts. Overexpression of endoglin resulted in an enhanced ACTA2, CCN2 and SERPINE1 mRNA response (p < 0.05). It also increased the mRNA and protein upregulation of the ECM components collagen type I (COL1A1) and fibronectin (FN1) (p < 0.05). Our results suggest that endoglin is an important mediator in the final common pathway of CKD and could be used as a possible new therapeutic target to counteract the progression towards end-stage renal disease (ESRD).

Herbal medicine in the management of renal disease: A comprehensive review of its potential for acute kidney injury, chronic kidney disease, diabetic nephropathy, and hypertension

“…Nephrotoxicants constitute a significant etiological factor contributing to the occurrence of AKI. Clinical studies have identified various agents, including cisplatin, gentamicin, glycerol, radiocontrast agents, and heavy metal ions such as mercury, as known nephrotoxic substances (1).…”

“…For instance, certain herbs possessing antioxidant, vasodilatory, and diuretic properties have demonstrated nephroprotective effects in cases of glycerol-induced AKI. Moreover, herbs with antimicrobial and anti-inflammatory properties can be employed in the management of sepsis-associated AKI (1,(11)(12)(13)(14).…”

“…While CKD frequently contributes to the progression towards end-stage renal disease (ESRD), it serves as a distinct and substantial risk factor for the development of CVD and represents the leading cause of mortality among individuals with CKD (1). An underlying commonality that encompasses all these syndromes is the presence of inflammation and oxidative stress.…”

“…An underlying commonality that encompasses all these syndromes is the presence of inflammation and oxidative stress. Two pivotal components play a crucial role in the progression of CKD: the primary etiology, particularly diabetes; and secondary contributing factors such as elevated blood pressure and proteinuria (1).…”

“…Each year, a considerable number of individuals are diagnosed with potentially life-threatening renal failure, encompassing acute kidney injury (AKI) and chronic kidney disease (CKD). They are closely linked disorders that are risk factors for each other and cardiovascular disease (CVD) (1). Figure 1 depicts the categorization of renal failure.…”