Cyclo(Val-Pro) and Cyclo(Leu-Hydroxy-Pro) from Pseudomonas sp. (ABS-36) alleviates acute and chronic renal injury under in vivo and in vivo models (Ischemic reperfusion and unilateral ureter obstruction)

The study aimed to identify small molecules having potentiality in alleviating renal injury. Two natural compounds cyclo(Val-Pro) (1) and cyclo(Leu-Hydroxy-Pro) (2) were first evaluated under acute renal injury model of ischemic reperfusion at different doses of 25, 50 and 75 mg/kg body weight. Further, the compounds were subjected to antimycin A-induced ischemic in vitro study (NRK-52E cell lines). Both the compounds significantly decreased plasma IL-1I3 levels (P < 0.05). Also, the mRNA expression levels of inflammatory markers (TNF-alpha, IL-6 and IL-1 beta) and renal injury markers (KIM-1, NGAL, alpha-GST and pi-GST) in the renal tissues were significantly alleviated (P < 0.01) along with the improvement in histological damage and control over neutrophil infiltration as a result of ischemic reperfusion. The in vitro study revealed the protective effect against antimycin A-induced cytotoxicity (P < 0.05) and antiapoptotic effect acting through the regulation of Bax, caspase 3 (pro and cleaved) and BCL2 with reduction in Annexin(+)PI(+) cells. Further, the compound cyclo(Val-Pro) (1) was evaluated (50 mg/ kg body weight dose) in chronic unilateral ureter obstruction model of renal injury in mice and TGF-beta-induced in vitro fibrotic model (NRK-49F cell lines). Cyclo(Val-Pro) (1) significantly reduced the expression levels of fibrotic markers (collagen-1, alpha-SMA and TGF-beta) and showed marked alleviation of renal fibrosis (sirius red staining). Also, the proliferation of TGF-beta-induced NRK-49F cells was significantly reduced along with decreased levels of collagen-1 and alpha-SMA in immunohistochemistry studies. In conclusion, the compounds significantly abrogated ischemic injury by inhibiting renal inflammation and tubular epithelial apoptosis. Further, cyclo (Val-Pro) (1) exhibited significant anti-fibrotic activity through the inhibition of fibroblast activation and proliferation. Thus, these proline-based cyclic dipeptides are recommended as drug leads for treating renal injury.

Automated summary

The study identified natural compounds that can alleviate renal injury by reducing inflammation and fibrosis markers. These compounds showed significant effects in decreasing plasma IL-1β levels, regulating mRNA expression levels of inflammatory and renal injury markers, and improving histological damage. The compounds also demonstrated protective and antiapoptotic effects in vitro, as well as significant anti-fibrotic activity. Therefore, these proline-based cyclic dipeptides are recommended as potential drug leads for treating renal injury.