State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China; Bioland Laboratory, Guangzhou, China.
State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China; Bioland Laboratory, Guangzhou, China.
Kidney Int. 2022 Sep;102(3):506-520. doi: 10.1016/j.kint.2022.04.028. Epub 2022 May 27.
Diabetic kidney disease (DKD) is one of the most common and devastating complications of diabetic mellitus, and its prevalence is rising worldwide. Klotho, an anti-aging protein, is kidney protective in DKD. However, its large size, prohibitive cost and structural complexity hamper its potential utility in clinics. Here we report that Klotho-derived peptide 6 (KP6) mimics Klotho function and ameliorates DKD. In either an accelerated model of DKD induced by streptozotocin and advanced oxidation protein products in unilateral nephrectomized mice or db/db mice genetically prone to diabetes, chronic infusion of KP6 reversed established proteinuria, attenuated glomerular hypertrophy, mitigated podocyte damage, and ameliorated glomerulosclerosis and interstitial fibrotic lesions, but did not affect serum phosphorus and calcium levels. KP6 inhibited β-catenin activation in vivo and blocked the expression of its downstream target genes in glomerular podocytes and tubular epithelial cells. In vitro, KP6 prevented podocyte injury and inhibited β-catenin activation induced by high glucose without affecting Wnt expression. Co-immunoprecipitation revealed that KP6 bound to Wnt ligands and disrupted the engagement of Wnts with low density lipoprotein receptor-related protein 6, thereby interrupting Wnt/β-catenin signaling. Mutated KP6 with a scrambled amino acid sequence failed to bind Wnts and did not alleviate DKD in db/db mice. Thus, our studies identified KP6 as a novel Klotho-derived peptide that ameliorated DKD by blocking Wnt/β-catenin. Hence, our findings also suggest a new therapeutic strategy for the treatment of patients with DKD.
糖尿病肾病（DKD）是糖尿病最常见和最具破坏性的并发症之一，其患病率在全球范围内呈上升趋势。Klotho 是一种抗衰老蛋白，对 DKD 具有肾脏保护作用。然而，其体积大、成本高、结构复杂，阻碍了其在临床中的潜在应用。在这里，我们报告 Klotho 衍生肽 6（KP6）模拟 Klotho 功能并改善 DKD。在单侧肾切除小鼠中由链脲佐菌素和高级氧化蛋白产物诱导的加速 DKD 模型或遗传上易患糖尿病的 db/db 小鼠中，慢性输注 KP6 可逆转已建立的蛋白尿，减轻肾小球肥大，减轻足细胞损伤，并改善肾小球硬化和间质纤维状病变，但不影响血清磷和钙水平。KP6 在体内抑制β-连环蛋白的激活，并阻断其在肾小球足细胞和肾小管上皮细胞中的下游靶基因的表达。在体外，KP6 可防止高糖诱导的足细胞损伤和β-连环蛋白的激活，而不影响 Wnt 的表达。共免疫沉淀显示 KP6 与 Wnt 配体结合并破坏 Wnts 与低密度脂蛋白受体相关蛋白 6 的结合，从而阻断 Wnt/β-连环蛋白信号通路。具有氨基酸序列混乱的突变 KP6 不能与 Wnts 结合，也不能减轻 db/db 小鼠的 DKD。因此，我们的研究鉴定出 KP6 是一种新型的 Klotho 衍生肽，通过阻断 Wnt/β-连环蛋白信号通路改善 DKD。因此，我们的发现也为治疗 DKD 患者提供了一种新的治疗策略。
