Kidney-Targeted Renalase Agonist Prevents Cisplatin-Induced Chronic Kidney Disease by Inhibiting Regulated Necrosis and Inflammation

Background Repeated administration of cisplatin causes chronic kidney disease (CKD). In previous studies, we reported that the kidney-secreted survival protein renalase and an agonist peptide protected mice from cisplatin-induced acute kidney injury. Methods To investigate whether kidney-targeted delivery of renalase might prevent cisplatin-induced CKD in a mouse model, we achieved specific delivery of a renalase agonist peptide (RP81) to the renal proximal tubule by encapsulating the peptide in mesoscale nanoparticles (MNPs). We used genetic deletion of renalase, single-cell RNA sequencing (RNA-seq) analysis, and Western blotting to determine efficacy and to explore underlying mechanisms. We also measured plasma renalase in patients with advanced head and neck squamous cell carcinoma receiving their first dose of cisplatin chemotherapy. Results In mice with CKD induced by cisplatin, we observed an approximate 60% reduction of kidney renalase; genetic deletion of renalase was associated with significantly more severe cisplatin-induced CKD. In this severe model of cisplatin-induced CKD, systemic administration of MNP-encapsulated RP81 (RP81-MNP) significantly reduced CKD as assessed by plasma creatinine and histology. It also decreased inflammatory cytokines in plasma and inhibited regulated necrosis in kidney. Single-cell RNA seq analyses revealed that RP81-MNP preserved epithelial components of the nephron and the vasculature, as well as suppressed inflammatory macrophages and myofibroblasts. In patients receiving their first dose of cisplatin chemotherapy, plasma renalase levels trended lower at day 14 post-treatment. Conclusions Kidney-targeted delivery of renalase agonist RP81MNP protects against cisplatin-induced CKD by decreasing cell death and improving the viability of the renal proximal tubule. These findings suggest that such an approach might mitigate the development of CKD in patients receiving cisplatin cancer chemotherapy.

Adhesion-GPCR Gpr116 (ADGRF5) expression inhibits renal acid secretion

The diversity and near universal expression of G protein-coupled receptors (GPCR) reflects their involvement in most physiological processes. The GPCR superfamily is the largest in the human genome, and GPCRs are common pharmaceutical targets. Therefore, uncovering the function of understudied GPCRs provides a wealth of untapped therapeutic potential. We previously identified an adhesion-class GPCR, Gpr116, as one of the most abundant GPCRs in the kidney. Here, we show that Gpr116 is highly expressed in specialized acid-secreting A-intercalated cells (A-ICs) in the kidney using both imaging and functional studies, and we demonstrate in situ receptor activation using a synthetic agonist peptide unique to Gpr116. Kidney-specific knockout (KO) of Gpr116 caused a significant reduction in urine pH (i.e., acidification) accompanied by an increase in blood pH and a decrease in pCO2compared to WT littermates. Additionally, immunogold electron microscopy shows a greater accumulation of V-ATPase proton pumps at the apical surface of A-ICs in KO mice compared to controls. Furthermore, pretreatment of split-open collecting ducts with the synthetic agonist peptide significantly inhibits proton flux in ICs. These data suggest a tonic inhibitory role for Gpr116 in the regulation of V-ATPase trafficking and urinary acidification. Thus, the absence of Gpr116 results in a primary excretion of acid in KO mouse urine, leading to mild metabolic alkalosis (“renal tubular alkalosis”). In conclusion, we have uncovered a significant role for Gpr116 in kidney physiology, which may further inform studies in other organ systems that express this GPCR, such as the lung, testes, and small intestine.