Durvasula Raghu V, Shankland Stuart J
Division of Nephrology, Box 356521, Univ. of Washington School of Medicine, Seattle, WA 98195, USA.
Am J Physiol Renal Physiol. 2005 Sep;289(3):F577-84. doi: 10.1152/ajprenal.00393.2004.
Glomerular capillary hypertension is a final common pathway to glomerulosclerosis. Because podocyte loss is an early event in the development of glomerulosclerosis, it is logical that the deleterious effects of glomerular capillary hypertension involve podocyte injury. Yet, the mechanisms by which elevated intraglomerular pressure is translated into a maladaptive podocyte response remain poorly understood. Secreted protein acidic and rich in cysteine (SPARC) is a matricellular protein activated in various disease states of the podocyte and accelerates renal injury, as evidenced by the milder course of experimental diabetic nephropathy in SPARC-null mice compared with diabetic SPARC wild-type mice. Accordingly, we tested the hypothesis that mechanical strain activates SPARC in podocytes and thus is a putative mediator of podocyte injury in states of intraglomerular capillary hypertension. Conditionally immortalized mouse podocytes were subjected to 10% cyclical stretch while nonstretched cells served as controls. SPARC levels were measured in whole cell lysate and cell media. Immunostaining was performed for SPARC in an experimental model of glomerular capillary hypertension. Our results demonstrate cyclical stretch of podocytes markedly increased SPARC levels in cell lysate, through activation of p38, as well as secreted SPARC. Relevance was shown by demonstrating increased podocyte staining for SPARC in the uninephrectomized spontaneously hypertensive rat. In conclusion, we have made the novel observation that mechanical forces characteristic of states of glomerular capillary hypertension lead to increased levels of SPARC in podocytes. We speculate that the increase in SPARC may be maladaptive and lead to a progressive reduction in podocyte number, thus fueling the future development of glomerulosclerosis.
肾小球毛细血管高压是肾小球硬化的最终共同途径。由于足细胞丢失是肾小球硬化发展过程中的早期事件，因此肾小球毛细血管高压的有害作用涉及足细胞损伤是合乎逻辑的。然而，肾小球内压力升高转化为足细胞适应性不良反应的机制仍知之甚少。富含半胱氨酸的酸性分泌蛋白（SPARC）是一种基质细胞蛋白，在足细胞的各种疾病状态中被激活，并加速肾损伤，与糖尿病SPARC野生型小鼠相比，SPARC基因敲除小鼠的实验性糖尿病肾病病程较轻就证明了这一点。因此，我们检验了以下假设：机械应变激活足细胞中的SPARC，因此是肾小球毛细血管高压状态下足细胞损伤的一个假定介质。将条件永生化的小鼠足细胞进行10%的周期性拉伸，未拉伸的细胞作为对照。在全细胞裂解物和细胞培养基中测量SPARC水平。在肾小球毛细血管高压的实验模型中对SPARC进行免疫染色。我们的结果表明，足细胞的周期性拉伸通过激活p38以及分泌SPARC，显著增加了细胞裂解物中的SPARC水平。在单侧肾切除的自发性高血压大鼠中，足细胞SPARC染色增加证明了其相关性。总之，我们有了一个新的发现，即肾小球毛细血管高压状态下的机械力导致足细胞中SPARC水平升高。我们推测，SPARC的增加可能是适应性不良的，并导致足细胞数量逐渐减少，从而推动肾小球硬化的未来发展。
