Hirudin attenuates puromycin aminonucleoside‐induced glomerular podocyte injury by inhibiting MAPK‐mediated endoplasmic reticulum stress

Abstract

Damage to podocytes is an important determinant of renal pathology. The puromycin aminonucleoside (PAN) mice nephropathy model is commonly used in the study of renal disease with podocyte injury. Hirudin has a broad nephroprotective effect and has been shown to treat renal interstitial fibrosis in previous studies. Mice were given PAN by gavage to prepare animal models, and MPC5 cells were incubated with PAN in vitro. Twenty-four hours urine was collected for analysis of urinary protein levels. Renal pathological changes were observed by hematoxylin and eosin staining. Immunofluorescence detection of nephrin in kidney tissues and cells. Apoptosis was analyzed with over TUNEL. Cytoskeleton, endoplasmic reticulum stress (ERS), p38 MAPK signaling, and apoptosis-related proteins were assessed by western blot analysis. The data suggested that hirudin attenuated reduced renal injury and increased urine protein in PAN mice. Hirudin also attenuated cytoskeletal protein (synaptopodin, nephrin, and podocin) disruption, ERS activation, and apoptosis in PAN mice and PAN-induced podocytes. In addition, hirudin inhibited the expression of p38 MAPK signaling key proteins upregulated by PAN, thereby suppressing ERS. The p38 MAPK agonist was able to partially antagonize the inhibition of p38 MAPK signaling by hirudin in PAN-induced podocytes, thereby reactivating the ERS inhibited by hirudin, promoting cytoskeletal protein degradation and increasing the level of apoptosis. In conclusion, hirudin could decrease podocyte injury by inhibiting p38 MAPK signaling-mediated ERS, resulting in the protection of the kidney from PAN damage. These findings may provide an experimental basis for hirudin treatment of podocyte injury diseases.

Unveiling Urinary Biomarkers, Crucial Genes, and Immune Infiltration in Lupus Nephritis Patients

“…It plays a crucial role in processes such as autophagosome formation and the transmission of oxidative and in ammatory signals [40]. In models of kidney disease, when external stimuli exceed the ER's steady-state, there is a signi cant increase in ER stress (ERS), which disrupts cytoskeletal proteins in podocytes [41]. ER dysfunction is associated with systemic lupus erythematosus (SLE), wherein enhancing the suppressive capacity of regulatory T cells (Tregs) can mitigate disease activity by inhibiting ERS.…”

Hirudin in the Treatment of Chronic Kidney Disease

“…It also mitigated the disruption of cytoskeletal proteins (synaptopodin, nephrin, and podocin), activation of endoplasmic reticulum stress (ERS), and apoptosis in both PAN mice and podocytes induced by PAN. This effect was achieved through the inhibition of p38 MAPK signaling-mediated ERS [ 80 ]. All evidence supports the protective effect of hirudin against podocyte injury.…”

“…[79] Inhibiting p38 MAPK signaling-mediated ERS [80] Acute kidney injury Inhibiting the interactions between thrombin and PAR [81] Table 2. Cont.…”

Research progress on the treatment of diabetic nephropathy with leech and its active ingredients

“…Another study indicated that hirudin increases the expression of podocalyxin and GLEPP1 in the apical region of podocytes under high glucose conditions, thus shielding podocytes and maintaining the integrity of the glomerular filtration barrier's structure and function (7). In puromycin aminonucleoside (PAN) mouse models and PAN-induced podocyte models, hirudin protects the kidneys and prevents proteinuria by suppressing the transmission of the p38 MAPK signaling pathway, reducing endoplasmic reticulum stress in podocytes, and attenuating the damage to the cytoskeletal proteins of podocytes by PAN (8).…”