Targets for Kidney

Understanding the molecular targets implicated in kidney pathogenesis is essential for deciphering the complex mechanisms underlying renal diseases, especially kidney cancers such as renal cell carcinoma (RCC), and other forms of nephropathy. The targets identified here—restricted to those with direct, evidence-based involvement in kidney disease—highlight key oncogenic signaling pathways (e.g., receptor tyrosine kinases, serine/threonine kinases), apoptotic regulators, drug resistance mechanisms, and epigenetic modifiers. Mechanistic insights into these targets reveal how aberrations in signaling, cell cycle control, apoptosis, and chromatin remodeling drive tumorigenesis, disease progression, and therapeutic resistance in the kidney. This knowledge enables the identification of actionable targets for drug development, supports the rational design of targeted therapies (e.g., kinase inhibitors, apoptosis modulators, epigenetic drugs), and informs biomarker discovery for diagnosis, prognosis, and therapy response. Collectively, these targets provide a molecular framework for precision medicine in kidney disease, supporting both the development of novel interventions and the optimization of existing therapeutic strategies.

Receptor Tyrosine Kinases (Rtks) And Downstream Signaling

This category encompasses receptor tyrosine kinases and their downstream effectors that are directly implicated in kidney oncogenesis and disease progression. Aberrant activation of these kinases (including EGFR, ERBB2, FLT1, FLT3, FLT4, BRAF, and RAF1) drives key oncogenic pathways such as MAPK/ERK and PI3K/AKT, promoting proliferation, survival, angiogenesis, and metastasis in kidney cancers. These targets are frequently altered in renal cell carcinoma and are central to current targeted therapeutic strategies.

Epidermal Growth Factor Receptor (EGFR)

Epidermal Growth Factor Receptor (EGFR) is a transmembrane RTK with extracellular ligand-binding, transmembrane, and intracellular tyrosine kinase domains. EGFR activation triggers the RAS-RAF-MEK-ERK and PI3K-AKT signaling cascades, driving cell proliferation, survival, and angiogenesis. EGFR overexpression and mutations have been reported in subsets of renal cell carcinoma (RCC), correlating with aggressive disease and poor prognosis (PMID: 15668712). EGFR inhibitors (e.g., erlotinib) have shown clinical benefit in some RCC cases, and EGFR is also being explored as a biomarker for therapy selection. Entrez: 1956; KEGG: 1956; UniProt: P00533.

Erb-B2 Receptor Tyrosine Kinase 2 (ERBB2)

Erb-B2 Receptor Tyrosine Kinase 2 (ERBB2/HER2) is a member of the EGFR family, lacking a direct ligand but forming heterodimers with other family members to activate downstream MAPK and PI3K/AKT pathways. ERBB2 overexpression is detected in a subset of aggressive RCCs and is associated with high-grade tumors and poor outcome (PMID: 14581316). HER2-targeted therapies (e.g., trastuzumab, lapatinib) are under investigation for RCC. Entrez: 2064; KEGG: 2064; UniProt: P04626.

Fms Related Receptor Tyrosine Kinase 1 (FLT1)

Fms Related Receptor Tyrosine Kinase 1 (FLT1/VEGFR1) is a VEGF receptor with a key role in angiogenesis. It contains seven immunoglobulin-like extracellular domains, a transmembrane region, and a split tyrosine kinase domain. FLT1 is overexpressed in RCC, contributing to the highly vascular nature of these tumors and supporting tumor growth and metastasis (PMID: 12039716). Anti-angiogenic therapies targeting VEGFRs (e.g., sunitinib, sorafenib) are mainstays in RCC treatment. Entrez: 2321; KEGG: 2321; UniProt: P17948.

Fms Related Receptor Tyrosine Kinase 3 (FLT3)

Fms Related Receptor Tyrosine Kinase 3 (FLT3) is a class III RTK with five extracellular immunoglobulin-like domains, a transmembrane segment, and a split tyrosine kinase domain. Although best known in hematologic malignancies, FLT3 expression is also detected in some RCCs, where it may contribute to tumor progression and therapy resistance (PMID: 22335897). FLT3 inhibitors are being explored in clinical trials. Entrez: 2322; KEGG: 2322; UniProt: P36888.

Fms Related Receptor Tyrosine Kinase 4 (FLT4)

Fms Related Receptor Tyrosine Kinase 4 (FLT4/VEGFR3) regulates lymphangiogenesis and is structurally similar to other VEGFRs. FLT4 is upregulated in RCC, particularly in tumors with high metastatic potential (PMID: 20531369). FLT4-targeted therapies are being developed to inhibit lymphatic spread. Entrez: 2324; KEGG: 2324; UniProt: P35916.

B-Raf Proto-Oncogene, Serine/Threonine Kinase (BRAF)

B-Raf Proto-Oncogene, Serine/Threonine Kinase (BRAF) is a serine/threonine kinase with a conserved kinase domain that functions downstream of RTKs in the MAPK pathway. Activating mutations of BRAF (e.g., V600E) are rare but have been identified in RCC, leading to constitutive MAPK signaling (PMID: 16723796). BRAF inhibitors are under investigation for RCC with BRAF alterations. Entrez: 673; KEGG: 673; UniProt: P15056.

Raf-1 Proto-Oncogene, Serine/Threonine Kinase (RAF1)

Raf-1 Proto-Oncogene, Serine/Threonine Kinase (RAF1/CRAF) is a serine/threonine kinase with a Ras-binding domain and a kinase domain, acting as a key effector in the MAPK/ERK pathway. Overexpression and activation of RAF1 have been linked to RCC progression and resistance to targeted therapies (PMID: 17332320). RAF inhibitors are being explored for therapeutic intervention. Entrez: 5894; KEGG: 5894; UniProt: P04049.

Apoptosis Regulation And Cell Survival

This category includes targets that regulate apoptosis and cell survival, processes critical for kidney cancer development and progression. BCL2 is a central anti-apoptotic protein whose dysregulation allows renal tumor cells to evade cell death, promoting tumor growth and resistance to therapy.

BCL2 Apoptosis Regulator (BCL2)

BCL2 Apoptosis Regulator (BCL2) is an integral outer mitochondrial membrane protein with BH domains that inhibit cytochrome c release and caspase activation. BCL2 overexpression is observed in a subset of RCCs and contributes to resistance to apoptosis, enhancing tumor survival and therapy resistance (PMID: 9486857). BCL2 inhibitors (e.g., venetoclax) are being evaluated in clinical trials for RCC. Entrez: 596; KEGG: 596; UniProt: P10415.

Drug Resistance And Transport

This category comprises membrane transporters involved in multidrug resistance, a major challenge in kidney cancer therapy. ABCB1 (P-glycoprotein) is upregulated in RCC, mediating efflux of chemotherapeutic agents and contributing to poor therapeutic response.

ATP Binding Cassette Subfamily B Member 1 (ABCB1)

ATP Binding Cassette Subfamily B Member 1 (ABCB1/P-glycoprotein/MDR1) is a transmembrane transporter with two nucleotide-binding domains and two transmembrane domains, mediating ATP-dependent efflux of xenobiotics and drugs. High expression of ABCB1 in RCC is linked to intrinsic and acquired multidrug resistance, limiting the efficacy of chemotherapy (PMID: 17332320). Inhibitors of ABCB1 are being explored to overcome resistance. Entrez: 5243; KEGG: 5243; UniProt: P08183.

Epigenetic Regulation

This category includes chromatin-modifying enzymes that regulate gene expression through epigenetic mechanisms. EZH2 is an H3K27 methyltransferase whose overexpression in RCC is associated with aggressive disease, stemness, and therapy resistance.

Enhancer of Zeste 2 Polycomb Repressive Complex 2 Subunit (EZH2)

Enhancer of Zeste 2 Polycomb Repressive Complex 2 Subunit (EZH2) is a SET domain-containing histone methyltransferase that catalyzes H3K27 trimethylation, leading to transcriptional repression. Overexpression of EZH2 in RCC correlates with high-grade tumors, metastasis, and poor prognosis (PMID: 21191034). EZH2 inhibitors are in clinical development for RCC. Entrez: 2146; KEGG: 2146; UniProt: Q15910.