Human kidney stone matrix proteins alleviate hyperoxaluria induced renal stress by targeting cell-crystal interactions

• Published in: Life sciences (1973) 2020-12, Vol.262, p.118498-16, Article 118498
• Main Authors: Narula, Shifa, Tandon, Simran, Kumar, Dhruv, Varshney, Swati, Adlakha, Khushboo, Sengupta, Shantanu, Singh, Shrawan Kumar, Tandon, Chanderdeep
• Format: Article
• Language: English
• Subjects: Apoptosis; Apoptosis - physiology; Arginine; Binding; Bone morphogenetic protein receptor type II; Calcium; Calcium oxalate; Calcium Oxalate - chemistry; Calcium oxalate monohydrate (COM); Calculi; Crystal-cell interactions; Crystallization; Disease Progression; Down-Regulation; Humans; Hyperoxaluria; Hyperoxaluria - complications; Immunocytochemistry; Inflammation; Inflammation - pathology; Inflammatory response; Ion channels; iTRAQ; Kidney - physiopathology; Kidney Calculi - chemistry; Kidney Calculi - pathology; Kidney stone matrix proteins; Kidney stones; Kidneys; Kinases; Macromolecules; Matrix protein; Methionine; Mitochondria; Nephrolithiasis; Network analysis; Oxalic acid; Polymerase chain reaction; Proteins; Proteins - chemistry; Proteins - metabolism; Proteomes; Reductases; Silica; Silicon dioxide; Stress, Physiological - physiology; Tenascin; Toxicity; Up-Regulation
• ISSN: 0024-3205; 1879-0631
• DOI: 10.1016/j.lfs.2020.118498

Increased levels of urinary oxalate also known as hyperoxaluria, increase the likelihood of kidney stone formation through enhanced calcium oxalate (CaOx) crystallization. The management of lithiatic renal pathology requires investigations at the initial macromolecular stages. Hence, the current study was designed to unravel the protein make-up of human kidney stones and its impact on renal cells' altered proteome, induced as the consequence of CaOx injury. CaOx kidney stones were collected from patients; stones were pooled for entire cohort, followed by protein extraction. Immunocytochemistry, RT-PCR and flow-cytometric analysis revealed the promising antilithiatic activity of kidney stone matrix proteins. The iTRAQ analysis of renal cells showed up-regulation of 12 proteins and down-regulation of 41 proteins due to CaOx insult, however, this differential expression was normalized in the presence of kidney stone matrix proteins. Protein network analysis revealed involvement of up-regulated proteins in apoptosis, calcium-binding, inflammatory and stress response pathways. Moreover, seven novel antilithiatic proteins were identified from human kidney stones' matrix: Tenascin-X-isoform2, CCDC-144A, LIM domain kinase-1, Serine/Arginine receptor matrix protein-2, mitochondrial peptide methionine sulfoxide reductase, volume-regulated anion channel subunit-LRRC8A and BMPR2. In silico analysis concluded that these proteins exert antilithiatic potential through crystal binding, thereby inhibiting the crystal-cell interaction, a pre-requisite to initiate inflammatory response. Thus, the outcomes of this study provide insights into the molecular events of CaOx induced renal toxicity and subsequent progression into nephrolithiasis. •The human kidney stone matrix proteins have an important role in modulating various processes of CaOx crystallization•We identified seven novel proteins from the matrix of CaOx kidney stones with promising activity against crystallization•Kidney stone matrix proteins normalized the differential expression of various proteins in COM treated renal cells