Haruhara Kotaro, Suzuki Toru, Wakui Hiromichi, Azushima Kengo, Kurotaki Daisuke, Kawase Wataru, Uneda Kazushi, Kobayashi Ryu, Ohki Kohji, Kinguchi Sho, Yamaji Takahiro, Kato Ikuma, Ohashi Kenichi, Yamashita Akio, Tamura Tomohiko, Tsuboi Nobuo, Yokoo Takashi, Tamura Kouichi
Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan; Division of Nephrology and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan.
Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
Kidney Int. 2022 May;101(5):912-928. doi: 10.1016/j.kint.2022.01.031. Epub 2022 Mar 1.
Although activation of the renin-angiotensin system and of its glomerular components is implicated in the pathogenesis of diabetic nephropathy, the functional roles of the tubular renin-angiotensin system with AT1 receptor signaling in diabetic nephropathy are unclear. Tissue hyperactivity of the renin-angiotensin system is inhibited by the angiotensin II type 1 receptor-associated protein ATRAP, which negatively regulates receptor signaling. The highest expression of endogenous ATRAP occurs in the kidney, where it is mainly expressed by tubules but rarely in glomeruli. Here, we found that hyperactivation of angiotensin II type 1 receptor signaling in kidney tubules exacerbated diabetic glomerular injury in a mouse model of streptozotocin-induced diabetic nephropathy. These phenomena were accompanied by decreased expression of CD206, a marker of alternatively activated and tissue-reparative M2 macrophages, in the kidney tubulointerstitium. Additionally, adoptive transfer of M2- polarized macrophages into diabetic ATRAP-knockout mice ameliorated the glomerular injury. As a possible mechanism, the glomerular mRNA levels of tumor necrosis factor-α and oxidative stress components were increased in diabetic knockout mice compared to non-diabetic knockout mice, but these increases were ameliorated by adoptive transfer. Furthermore, proximal tubule-specific ATRAP downregulation reduced tubulointerstitial expression of CD206, the marker of M2 macrophages in diabetic mice. Thus, our findings indicate that tubular ATRAP-mediated functional modulation of angiotensin II type 1 receptor signaling modulates the accumulation of tubulointerstitial M2 macrophages, thus affecting glomerular manifestations of diabetic nephropathy via tubule-glomerular crosstalk.
尽管肾素-血管紧张素系统及其肾小球成分的激活与糖尿病肾病的发病机制有关，但肾小管肾素-血管紧张素系统及其AT1受体信号在糖尿病肾病中的功能作用尚不清楚。肾素-血管紧张素系统的组织活性过高可被血管紧张素II 1型受体相关蛋白ATRAP抑制，该蛋白可负向调节受体信号。内源性ATRAP的最高表达出现在肾脏，主要由肾小管表达，而在肾小球中很少表达。在此，我们发现在链脲佐菌素诱导的糖尿病肾病小鼠模型中，肾小管中血管紧张素II 1型受体信号的过度激活加剧了糖尿病肾小球损伤。这些现象伴随着肾小管间质中CD206表达的降低，CD206是替代性激活和组织修复性M2巨噬细胞的标志物。此外，将M2极化巨噬细胞过继转移到糖尿病ATRAP基因敲除小鼠中可改善肾小球损伤。作为一种可能的机制，与非糖尿病基因敲除小鼠相比，糖尿病基因敲除小鼠中肿瘤坏死因子-α和氧化应激成分的肾小球mRNA水平升高，但过继转移可改善这些升高。此外，近端小管特异性ATRAP下调降低了糖尿病小鼠肾小管间质中M2巨噬细胞标志物CD206的表达。因此，我们的研究结果表明，肾小管ATRAP介导的血管紧张素II 1型受体信号功能调节可调节肾小管间质M2巨噬细胞的积聚，从而通过肾小管-肾小球相互作用影响糖尿病肾病的肾小球表现。
