Chen Bohan, Alam Zubia, Ge Yan, Dworkin Lance, Gong Rujun
Division of Nephrology, Department of Medicine, University of Toledo Medical Center, Toledo, OH, United States.
The Center for Diabetes and Endocrine Research, University of Toledo, Toledo, OH, United States.
Front Physiol. 2022 Jun 1;13:887641. doi: 10.3389/fphys.2022.887641. eCollection 2022.
Clinical evidence indicates that the melanocortin peptide ACTH is effective in inducing remission of nephrotic glomerulopathies like minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS), including those resistant to steroids. This suggests that a steroid-independent melancortinergic mechanism may contribute. However, the type of melanocortin receptor (MCR) that conveys this beneficial effect as well as the underlying mechanisms remain controversial. Burgeoning evidence suggests that MC5R is expressed in glomeruli and may be involved in glomerular pathobiology. This study aims to test the effectiveness of a novel highly selective MC5R agonist (MC5R-A) in puromycin aminonucleoside (PAN) nephrosis. Upon PAN injury, rats developed evident proteinuria on day 5, denoting an established nephrotic glomerulopathy. Following vehicle treatment, proteinuria continued to persist on day 14 with prominent histologic signs of podocytopathy, marked by ultrastructural glomerular lesions, including extensive podocyte foot process effacement. Concomitantly, there was loss of podocyte homeostatic markers, such as synaptopodin and podocin, and expression of the podocyte injury marker desmin. Treatment with MC5R-A attenuated urine protein excretion and mitigated the loss of podocyte marker proteins, resulting in improved podocyte ultrastructural changes. in cultured podocytes, MC5R-A prevented the PAN-induced disruption of actin cytoskeleton integrity and apoptosis. MC5R-A treatment in PAN-injured podocytes also reinstated inhibitory phosphorylation and thus averted hyperactivity of GSK3β, a convergent point of multiple podocytopathic pathways. Collectively, pharmacologic activation of MC5R by using the highly selective small-molecule agonist is likely a promising therapeutic strategy to improve proteinuria and glomerular injury in protenuric nephropathies.
临床证据表明，促黑素肽促肾上腺皮质激素（ACTH）可有效诱导肾病性肾小球病（如微小病变病（MCD）和局灶节段性肾小球硬化（FSGS））缓解，包括对类固醇耐药的病例。这表明可能存在一种不依赖类固醇的促黑素能机制。然而，传达这种有益作用的促黑素受体（MCR）类型以及潜在机制仍存在争议。越来越多的证据表明，MC5R在肾小球中表达，可能参与肾小球病理生物学过程。本研究旨在测试新型高选择性MC5R激动剂（MC5R-A）在嘌呤霉素氨基核苷（PAN）肾病中的有效性。在PAN损伤后，大鼠在第5天出现明显蛋白尿，表明已形成肾病性肾小球病。给予溶剂对照处理后，蛋白尿在第14天持续存在，伴有明显的足细胞病组织学特征，以肾小球超微结构病变为标志，包括广泛的足细胞足突消失。同时，足细胞稳态标志物（如突触素和足蛋白）丢失，足细胞损伤标志物结蛋白表达。用MC5R-A治疗可减少尿蛋白排泄，减轻足细胞标志物蛋白的丢失，从而改善足细胞超微结构变化。在培养的足细胞中，MC5R-A可防止PAN诱导的肌动蛋白细胞骨架完整性破坏和细胞凋亡。在PAN损伤的足细胞中用MC5R-A治疗还可恢复抑制性磷酸化，从而避免GSK3β过度激活，GSK3β是多种足细胞病途径的汇聚点。总的来说，使用高选择性小分子激动剂对MC5R进行药理学激活可能是改善蛋白尿性肾病中蛋白尿和肾小球损伤的一种有前景的治疗策略。
