The kidney tubular apparatus in mammals comprises several distinct segments, each performing an indispensable function in kidney physiology [17,18]. These segments include the proximal tubule, loop of Henle, distal tubule, connecting tubule, and collecting duct, each characterized by specific structural and functional attributes [19,20]. The proximal tubule, which consists of convoluted and straight portions, features cuboidal epithelial cells with a brush border [21,22]. The loop of Henle includes the proximal tubule’s pars recta, descending thin limb, ascending thin limb, and thick ascending limb (TAL) [23,24]. The distal tubule consists of the TAL, macula densa, distal convoluted tubule (DCT), and connecting tubules [25,26]. Finally, the collecting duct, which comprises various segments, contains principal and intercalated cells.

EGFR expression is observed in normal kidneys, where it is widely distributed across various segments, including proximal tubule, thin limb of the loop of Henle, TAL, DCT, and collecting duct, and glomerulus. Specifically, within the glomerulus, EGFR expression is found in podocytes, endothelial cells, mesangial cells, and along the glomerular basement membrane [27,28] (Table 1). Additionally, EGFR expression is present in medullary interstitial cells, peritubular capillaries, and arterioles in the kidneys [27,28]. In tubular epithelial cells, EGFR is predominantly localized to the basolateral membrane and the cytoplasm adjacent to the basal membrane [27,29]. Upon binding of a EGFR ligand, EGFR activation through tyrosine phosphorylation significantly increases at the basolateral membrane across all segments of the kidney tubules, including proximal tubules, where EGFR expression is faint under normal conditions [30–32]. Notably, EGFR activation is highest in proximal straight tubules, followed by proximal convoluted tubules, collecting ducts, and DCT [31,32].

The first ligand discovered for the EGFR was epidermal growth factor (EGF) [33,34]. This ligand was initially characterized by Nobel laureate Dr. Stanley Cohen and his colleagues, who identified it in an extract from the submaxillary gland [35,36]. In addition to EGF, several other ligands interact with EGFR, including transforming growth factor-α (TGF-α), amphiregulin, epigen, heparin-binding EGF-like growth factor (HB-EGF), epiregulin, and betacellulin [37,38]. These ligands can be categorized into two groups [39]: the first group, which includes EGF, TGF-α, amphiregulin, and epigen, binds specifically to EGFR, while the second group, comprising HB-EGF, epiregulin, and betacellulin, binds to both EGFR and human epidermal growth factor receptor 4 (HER4). Connective tissue growth factor (CTGF), recognized as a ligand for integrins and TGF-β receptors, can also bind to and activate EGFR [40,41]. Among these ligands, EGF, TGF-α, HB-EGF, and betacellulin are considered high-affinity ligands [42,43], whereas amphiregulin, epigen, and epiregulin are classified as low-affinity ligands [43,44].

All endogenous EGFR ligands, with the exception of CTGF, are initially expressed as type I transmembrane proteins. These ligands are then converted into their mature, soluble forms, which are released into the extracellular environment through proteolytic cleavage by metalloproteinases, particularly members of the a disintegrin and metalloproteinase (ADAM) family [45,46]. Most EGFR ligands are produced in the kidney. EGF is primarily found in the TAL and DCT, with immunoreactivity observed along the apical membrane and in the cytoplasm [27,47]. In the connecting tubule and cortical collecting duct, EGF exhibits membranous staining, particularly in intercalated cells, which display a distinctive octopus-like morphology [47]. TGF-α is predominantly localized in the proximal tubules of the kidney cortex [47,48], with additional presence in the DCT [48]. HB-EGF is mainly localized in the proximal tubule, especially in the S3 segment of the outer stripe of the outer medulla [49]. Amphiregulin is expected to be primarily expressed in the proximal and distal tubules, as demonstrated by its upregulation following kidney injuries [50,51], although detailed distribution along various tubular segments is limited. Epigen has been detected in mouse kidney tissues [52], epiregulin is expressed in primary cultured human glomerular mesangial cells [53], and betacellulin is expressed in bovine kidney epithelial cell [54]. However, there are no reports detailing the expression of these proteins along specific tubular segments.

Activation of the EGFR depends on its ligands, which promote the formation of either homo- or heterodimers at the cellular membrane, ultimately leading to receptor internalization. Upon ligand binding, EGFR can dimerize with another EGFR molecule (homodimerization) or with a different receptor of the human epidermal growth factor receptor (HER) family (heterodimerization) [7,8]. Although EGFR has also been shown to heterodimerize with receptors for hepatocyte growth factor (HGF), insulin-like growth factor-1 (IGF-1), and platelet-derived growth factor (PDGF) [55,56], the biologic significance of these interactions remains unclear. Following internalization, the dimerized receptors undergo autophosphorylation within their intracellular tyrosine kinase domains, generating binding sites for signaling molecules and initiating downstream intracellular signaling cascades [8,10]. Multiple post-translational modifications of EGFR, including methylation of the extracellular domain [57,58], phosphorylation on Serine and Threonine residues [57,59], SUMOylation [57,60], and ubiquitination [61,62], have been identified as regulatory factors that influence EGFR functionality and may serve as potential therapeutic targets to overcome drug-resistance mutations [63,64].

EGFR plays a crucial role in various signaling pathways that regulate cell growth, differentiation, and survival, particularly in kidney disease [30]. Following EGFR autophosphorylation, it activates downstream pathways such as mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK), which promote cell proliferation, and phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT), which enhances cell survival by inhibiting apoptosis [2,65]. Additionally, HER2, a member of the EGFR family, can form heterodimers with EGFR, intensifying signaling and contributing to kidney injury and fibrosis [30,66]. EGFR signaling is critical in kidney development and repair processes, promoting the proliferation of kidney epithelial cells and facilitating recovery following acute kidney injury (AKI) [30,67]. However, dysregulation of EGFR signaling is linked to chronic kidney disease (CKD), where it can exacerbate inflammation and fibrosis [13,68]. Consequently, targeting EGFR has been explored as a therapeutic strategy for various kidney diseases, particularly those associated with fibrosis. Dual targeting of EGFR and HER2 may offer potential benefits in conditions where both pathways are implicated.

Small molecules inhibit the activity of EGFR tyrosine kinase by binding to the ATP-binding site within the receptor’s intracellular domain [69]. EGFR tyrosine kinase inhibitors (TKIs) specifically target this domain of EGFR, competing with ATP for binding [69]. This inhibition prevents the activation of tyrosine kinase and the autophosphorylation of EGFR, thereby disrupting EGFR signal transduction pathways [69,70]. By preventing receptor phosphorylation, which is essential for the activation of downstream signaling pathways, TKIs effectively inhibit EGFR activation [70,71] (Table 2). As shown in, these inhibitors can selectively interfere with EGFR alone or with other human epidermal growth factor receptor (HER) family receptors in addition to EGFR. Numerous TKIs currently in clinical development have demonstrated potential antitumor activity. Furthermore, TKIs have shown protective effects against various kidney diseases in animal studies. These inhibitors can be further categorized based on whether their effects are reversible or irreversible [4,72].

Several studies have highlighted the role of EGFR in various animal models of kidney disease (Table 3), encompassing a wide range of conditions. These include ischemic kidney disease such as AKI and CKD induced by unilateral or bilateral kidney ischemia and reperfusion injury (IRI); septic AKI triggered by lipopolysaccharide or cecal ligation and puncture; metabolic kidney disease such as hyperuricemia, diabetic nephropathy, and obesity-induced nephropathy; inflammatory kidney disease such as glomerulonephritis, lupus nephritis, and inflammation induced by tumor necrosis factor-like weak inducer of apoptosis (TWEAK); and obstructive kidney disease such as unilateral ureteral obstruction (UUO).

IRI contributes to the development of AKI, characterized by a sudden decline in kidney function, tubular injury, and inflammation [99–101]. In cases where recovery is maladaptive, the initial AKI can progress to CKD due to chronic inflammation and tubulointerstitial fibrosis [86,102,103]. Bilateral kidney IRI induces kidney dysfunction and tubular injury; however, pharmacological and proximal tubule-specific inhibition of EGFR does not significantly affect kidney dysfunction and tubular injury in AKI induced by bilateral kidney IRI [79,86]. Conversely, unilateral kidney IRI exacerbates tubular injury and apoptosis in the tubules when EGFR is inhibited due to a point mutation in the Egfr gene (Waved-2 mutation) [85]. Pharmacological inhibition of EGFR has been demonstrated to reduce the pro-inflammatory response, as evidenced by decreased infiltration of macrophages and lymphocytes, as well as lower levels of pro-inflammatory mRNA expression following bilateral kidney IRI [86] and kidney transplantation [87]. Additionally, EGFR inhibition has been found to decrease IRI-induced activation of AKT and ERK [79,85], which may contribute to delayed recovery of kidney function and tubular morphology [79]. Generally, EGFR inhibition effectively reduces tubulointerstitial fibrosis following IRI and kidney transplantation [85–87].

Sepsis can lead to AKI through mechanisms such as hypotension, which impairs kidney perfusion and causes ischemia [104,105]. Additionally, the systemic inflammatory response in sepsis releases pro-inflammatory cytokines and mediators that can directly damage kidney tissues [104,106]. In mouse models of septic AKI induced by lipopolysaccharide or cecal ligation and puncture (CLP), studies have demonstrated that inhibiting EGFR, either pharmacologically or genetically, offers protection against the pro-inflammatory response [75,80]. This protective effect is evidenced by a reduction in macrophage infiltration, decreased pro-inflammatory mRNA expression [75,80]. This protection is associated with less severe kidney dysfunction, tubular injury [75], and mortality [80].

Numerous animal studies have explored EGFR-targeted inhibition in diabetic nephropathy [82,92,93]. Both genetic and pharmacological inhibition of EGFR ultimately improve Type 2 diabetes by reducing blood glucose levels [92], but this effect is not observed in Type 1 diabetes [77,82,93]. In both types of diabetes, EGFR inhibition consistently reduces albuminuria [82,92,93], leading to the amelioration of diabetes-induced kidney dysfunction. In diabetic mice subjected to EGFR inhibition, the kidneys exhibit reduced histopathological injury in the tubules, decreased collagen deposition in the interstitial areas [82,92,93], and reduced infiltration of leukocytes, including macrophages [77,92] and T lymphocytes [92]. Glomeruli also show improvements, including reduced loss of podocytes [90,92,93], decreased cell cycle arrest [88], reduced macrophage infiltration [92], less mesangial expansion [93], and diminished glomerulosclerosis [77,92,93] during diabetic nephropathy. Interestingly, specific deficiencies of Egfr in podocytes [93] and proximal tubules [90] completely mitigate tubulointerstitial fibrosis. However, conflicting results exist regarding the effect of EGFR inhibition on tubular apoptosis [82,84,90]. Diabetic rats treated with PKI-166 exhibit increased apoptotic cell death in the tubules [84], while diabetic mice treated with AG-1478 show decreased apoptotic cell death in the tubules [82]. This controversy underscores the necessity for further research into the relationship between EGFR and apoptosis in diabetic kidneys. Treatment with gefitinib attenuates kidney dysfunction, histopathological injury in the tubules, and tubulointerstitial fibrosis induced by hyperuricemia from adenine and potassium oxonate [74]. Additionally, obesity-induced nephropathy is characterized by increased apoptosis and fibrosis, but treatment with AG-1478 effectively mitigates these symptoms [83].

In inflammatory kidney diseases, the role of EGFR has been primarily studied in models of glomerulonephritis and lupus nephritis [107,108]. Pharmacological inhibition of EGFR effectively enhances kidney function in cases of glomerulonephritis [73,78,94]. This inhibition also reduces crescent formation and macrophage infiltration in the glomeruli affected by glomerulonephritis [78,94]. Notably, specific deficiencies of Egfr in podocytes [78] and macrophages [73] protect against these symptoms during glomerulonephritis. In contrast, the effects of pharmacological EGFR inhibition in lupus nephritis models remain controversial. Treatment with erlotinib has been shown to reduce kidney dysfunction and tubulointerstitial fibrosis in lupus nephritis induced by Fcgr2b deficiency [95]. Conversely, treatment with lapatinib exacerbates kidney dysfunction and tubulointerstitial fibrosis in lupus nephritis induced by interferon-α administration [81]. Additionally, Egfr deficiency in CD4-positive T cells worsens glomerular and tubulointerstitial injuries in pristane-induced lupus nephritis [96]. On the other hand, treatment with erlotinib alleviates inflammation by decreasing macrophage and T cell infiltrations, as well as reducing the expression of cytokines and chemokines in kidneys affected by inflammation induced by TWEAK [97]. Further studies are necessary using animal models of lupus nephritis to gain a deeper understanding of the varying effects based on the type of disease model and the inhibition strategy employed.

Obstructive kidney disease occurs when a blockage in the urinary tract impedes urine flow, leading to increased pressure in the kidneys [109,110]. Over time, this obstruction can damage the kidneys, potentially resulting in CKD [111,112]. UUO is a specific type of obstructive kidney disease characterized by the obstruction of one ureter [110,113,114]. UUO can be caused by various factors, including kidney stones, tumors, or congenital abnormalities [111,113]. This condition leads to increased collagen deposition and the expression of pro-fibrotic proteins, resulting in tubulointerstitial fibrosis [112,113]. However, EGFR inhibition through treatment with gefitinib, EGFR point mutations, or EGFR mimotopes has been shown to effectively reduce fibrosis [68,76,98]. Additionally, these interventions mitigate kidney inflammation, as indicated by reduced macrophage infiltration and lower levels of pro-inflammatory mRNA expression during UUO [68,76,98].