From the Guidelines
The extracellular matrix (ECM) secreted in the kidneys primarily consists of uromodulin, a protein uniquely expressed in the kidney by cells of the thick ascending limbs (TAL) and early distal convoluted tubules (DCT) 1. This protein is secreted in the urine as one of the most abundant urinary proteins that is uniquely made and released by the kidney. The kidney produces and secretes two distinct forms of uromodulin: polymerizing uromodulin and non-polymerizing uromodulin, which are released through different pathways and have different physiological roles 1. Key points about uromodulin include:
- It is produced by kidney cells, including those in the TAL and DCT
- It is secreted in the urine and also released into the renal interstitium and circulation
- It has been implicated in regulating salt reabsorption, cation homeostasis, hypertension, acute kidney injury, chronic kidney disease, urinary defense, systemic inflammation and stress, immunomodulation, and kidney stone disease 1
- Abnormal uromodulin production or function can lead to kidney diseases, such as autosomal dominant tubulo-interstitial disease (ADTKD-UMOD) 1 The functions of uromodulin are likely to be pleotropic, depending on its location, form, and interaction with specific molecules, cells, and structures 1. Overall, uromodulin plays a crucial role in maintaining a healthy renal milieu, and its dysregulation can lead to various kidney diseases.
From the Research
ECM Composition in the Kidneys
The extracellular matrix (ECM) in the kidneys is a complex network of proteins that provides a scaffold and organ stability, and its composition is determined by the function of each of the histological compartments of the kidney, including glomeruli, tubulo-interstitium, and vessels 2. The major components of the ECM in the kidneys include:
- Collagens
- Elastin
- Glycoproteins
- Proteoglycans
- Fibronectin
- Laminin
- Fibrillins
- Fibulins
- Matrilins
- Tenascins
- Thrombospondins
ECM Proteins Involved in Kidney Fibrosis
Kidney fibrosis is characterized by the pathological deposition of ECM proteins, and several ECM proteins have been identified as potential biomarkers of renal fibrosis, including:
- Glutathione peroxidase 3 (GPX3) 3
- Collagen
- Laminin
- Fibronectin
- Elastin
Role of ECM in Kidney Diseases
The ECM plays a critical role in the development of kidney diseases, including diabetic nephropathy, and the accumulation of ECM proteins leads to glomerular and tubular basement membranes thickening and increase of mesangial matrix, ultimately resulting in glomerulosclerosis and tubulointerstitial fibrosis 4. The ECM also regulates cellular functions such as adhesion, differentiation, migration, stability of phenotype, and resistance towards apoptosis 5.
ECM Remodeling in Kidney Fibrosis
The ECM undergoes dynamic changes in composition and contents during the evolution of chronic kidney disease (CKD), and ECM remodeling is a key feature of kidney fibrosis 3. The proteomic landscape of the ECM in the fibrotic kidney has been characterized, and several signature proteins have been identified, including GPX3, which plays a role in establishing an oxidatively stressed, profibrotic, proinflammatory and antiangiogenetic microenvironment 3.