The real culprit behind diabetic nephropathy: impaired renal autoregulation?

More than 29 million of Americans have diabetes. About 30–40% of the diabetic patients will eventually develop diabetic nephropathy (DN), which is the leading cause of end-stage renal disease (Centers for Disease Control and Prevention, 2014; United States Renal Data System., 2012). Control of blood pressure (BP) and blood glucose has been shown to reduce the risk of developing DN (Nathan 2014). However, not all patients with poor control in BP and plasma glucose will develop renal disease. On the other hand, over 1/3 of patients with type 2 diabetes develop DN despite strict control of BP and/or blood glucose (Mooyaart 2014; Tomino and Gohda 2015). Therefore, further understanding the pathophysiological mechanisms underlying the DN is essential to identify potential target for treatment. Many studies demonstrated an association between glomerular capillary hypertension and diabetes-associated kidney disease. An elevated glomerular capillary pressure was first reported in experimental diabetic Munich-Wistar rats in 1980s (Hostetter et al. 1982). In physiological conditions, glomerular capillary pressure is well-maintained within a normal range by a renal autoregulatory mechanism, by which the renal blood flow (RBF) and glomerular filtration rate (GFR) maintain constant and are independent of systemic blood pressure over a wide range. While its mechanism and significance have not been fully elucidated, renal autoregulation is considered an essential mechanism to keep constant electrolytes delivery to distal nephrons and sustain normal kidney clearance function facing fluctuations in systemic blood pressure. Renal autoregulation is also proposed to be a unique self-protective mechanism of the kidney in our body, which isolate fluctuations in systemic blood pressure and keep a relatively constant level in intraglomerular capillary pressure that may prevent glomerular injuries. The renal autoregulation is believed to be mainly mediated by myogenic response of the afferent arteriole and tubuloglomerular feedback (TGF) response. Myogenic response is rapid response of vasoconstriction of the afferent arteriole in response to an increase in transmural pressure. TGF response refers a negative feedback mechanism that increased NaCl delivery to the macula densa promotes release of adenosine and/or ATP, which constricts the afferent arteriole and decreases single nephron GFR (Burke et al. 2014). Impaired autoregulation has been proposed to play an important role in the development of kidney injury by elevation of glomerular capillary pressure in hypertensive experimental models. Typical examples are Dahl salt-sensitive rats and spontaneously hypertensive (SHR) rats. Dahl salt-sensitive rats exhibit impaired autoregulation and are sensitive to diabetic kidney injury, whereas SHR rats show intact autoregulation and are resistant to diabetic kidney injury in the present of hypertension (Slaughter et al. 2013). However, whether the impaired autoregulation itself without hypertension induces diabetic kidney injury remains elusive. It has long been reported that Milan normotensive strain (MNS) of rats develops progressive proteinuria and glomerular injury following the induction of diabetes with streptozotocin (STZ) (Pugliese et al. 2005) in the absence of systemic hypertension. In contract, Milan hypertensive strain (MHS) of rats is resistant to the development of proteinuria and kidney injury. The mechanisms underlying have not been clarified. A recent study by Ge et al. (2016) provided a potential mechanism for the difference in diabetes-associated kidney injury between MNS and MHS rats. They demonstrated that normotensive rats with impaired autoregulation developed severe diabetic kidney injury, in contrast, the hypertensive rats with intact autoregulation were protected from diabetic kidney injury. Renal autoregulation was evaluated by measurement of myogenic response of the afferent arteriole (Af-Art), RBF and stop-flow pressure of proximal tubule when perfusion pressure was increased in MNS and MHS rats. While MHS exhibited efficient renal autoregulatory function, autoregulation in MNS was impaired. Then type 1 diabetes was induced with STZ and plasma glucose levels were maintained at a similar level in both groups of