Diabetes Volume 66, April 2017 791 Richard E. Gilbert Proximal Tubulopathy: Prime Mover and Key Therapeutic Target in Diabetic Kidney Disease Diabetes 2017;66:791–800 | DOI: 10.2337/db16-0796 The current view of diabetic kidney disease, based on estimated glomerular filtration rate (eGFR) decline (2). In meticulously acquired ultrastructural morphometry and recognition of these findings, the term diabetic kidney the utility of measuring plasma creatinine and urinary al- disease rather than diabetic nephropathy is now commonly bumin, has been almost entirely focused on the glomer- used. On the background of recent advances in the role of ulus. While clearly of great importance, changes in the the proximal tubule as a prime mover in diabetic kidney PERSPECTIVES IN DIABETES glomerulus are not the major determinant of renal prog- pathology, this review highlights key recent developments. nosis in diabetes and may not be the primary event in the Published mostly in the general scientific and kidney- development of diabetic kidney disease either. Indeed, specific literature, these advances highlight the pivotal advances in biomarker discovery and a greater appreci- role this part of the nephron plays in the initiation, pro- ation of tubulointerstitial histopathology and the role of gression, staging, and therapeutic intervention in diabetic tubular hypoxia in the pathogenesis of chronic kidney kidney disease. From a pathogenetic perspective, as illus- disease have given us pause to reconsider the current trated in Fig. 1 and as elaborated on further in this review, “glomerulocentric” paradigm and focus attention on the proximal tubule that by virtue of the high energy require- tubular hypoxia as a consequence of increased energy de- ments and reliance on aerobic metabolism render it par- mands and reduced perfusion combine with nonhypoxia- ticularly susceptible to the derangements of the diabetic related forces to drive the development of tubular atrophy fi state. Such findings raise important issues for therapeu- and interstitial brosis in a vicious cycle that promotes tic advances specifically targeting the pathophysiological disease progression in diabetes. These insights offer new perturbations that develop in this part of the nephron. opportunities for therapeutic development. NORMAL AND DISORDERED STRUCTURE The description of diffuse and nodular glomerulosclerosis Anatomically, the proximal tubule refers to that part of the by Kimmelstiel and Wilson in 1936 (1) set investigation nephron that is directly contiguous with the parietal epi- on a course that has since focused primarily on the glo- thelium of Bowman’s capsule. Measuring approximately merulus as a means of understanding the pathogenesis of 14 mm in length in humans, it consists of three subtly dis- diabetic kidney disease. Changes in glomerular structure tinct segments. The S1 segment comprises the first two- such as mesangial expansion, reduction in capillary surface, thirds of the tubule’s early, convoluted component (pars and podocyte loss are undoubtedly major features of dia- convoluta); the S2 includes the final portion of the pars betic kidney disease that help differentiate it from other convoluta along with the initial, cortical part of its straight forms of glomerulonephritis. These findings are, however, component (pars recta); and the S3 makes up the remain- juxtaposed with the more recent knowledge that some der of the pars recta as it dives deeply into the cortex and patients with advanced disease display neither substantial outer medulla (3). glomerular pathology nor proteinuria and that kidney Cells in the S1 segment are characterized by a tall apical function declines well before traditional indicators of kid- brush border, prominent basolateral invaginations, exten- ney disease such as microalbuminuria or creatinine-based sive endocytic-lysosomal apparatus, and abundant, often Keenan Research Centre for Biomedical Science and Li Ka Shing Knowledge © 2017 by the American Diabetes Association. Readers may use this article as Institute of St. Michael’s Hospital, Toronto, Canada long as the work is properly cited, the use is educational and not for profit, and the Corresponding author: Richard E. Gilbert, [email protected]. work is not altered. More information is available at http://www.diabetesjournals .org/content/license. Received 30 June 2016 and accepted 2 January 2017. 792 Proximal Tubulopathy and Diabetic Kidney Disease Diabetes Volume 66, April 2017 Figure 1—Proximal tubule and the pathogenesis of diabetic kidney disease. As a consequence of increased consumption, impaired utilization, and reduced delivery of O2, the proximal tubule, by virtue of its high energy requirements and reliance on aerobic metabolism, is susceptible to ischemic injury in diabetes. These pathophysiological disturbances combine with nonischemic mechanisms to induce apoptosis and fibrosis in this part of the nephron that together lead to chronic loss of function and a propensity to AKI. Moreover, the diabetes-induced injury to the proximal tubule may in turn lead to glomerular pathology and postglomerular hypoperfusion, while fibrotic expansion of the interstitium compresses and further disrupts the local microvasculature. RAS, renin-angiotensin system. elongated, mitochondria. In the S2, epithelial cells have atubular glomeruli (5). Such changes are commonly ob- shorter brush borders, less prominent basolateral invagi- served in patients with type 1 diabetes with overt protein- nations, and smaller mitochondria, while in the S3 baso- uria; Najafian et al. (6) noted that in patients with normal lateral invaginations are absent and mitochondria are to moderately impaired GFR, 17% of glomeruli were atubular fewer (3) (Fig. 2). and an additional 51% were attached to atrophic tubules The proximal tubule undergoes a range of structural (Fig. 3). Similar findings have also been reported in type changes in diabetes such as tubular atrophy, interstitial 2 diabetes, where atubular glomeruli were found in 7% fibrosis, and peritubular capillary rarefaction, each of which of patients with diabetes, with a further 26% showing correlate closely with declining kidney function (4). Addi- glomerulotubular junction abnormalities even in the ab- tional dysfunction occurs when, as in cystinosis, atrophy sence of significant proteinuria so that extent of such occurs at the critical junction between Bowman’scapsule abnormalities correlated inversely with creatinine clear- and the proximal tubule, giving rise to nonfunctioning ance (r = 20.70, P = 0.011) (7). Figure 2—Transmission electron micrographs of the proximal tubule of the rhesus monkey. The S1 segment (left) shows a typical tall columnar cell with numerous elongated mitochondrial profiles (M) enclosed within plications of the basal plasmalemma. Apical system of vesicles, vacuoles, and dense tubules are well developed. Magnification 39,165. In S2 (center), the brush border is more irregular with occasional skip areas (arrow). Apical vesicles and dense tubules are not as extensively developed, but apical vacuoles are more prominent. The cell is low columnar, and lateral interdigitations with adjacent cells are less complex. Magnification 38,900. Cells in S3 (right) are cuboidal and continue to exhibit a well-developed brush border. Apical dense tubules and apical vacuoles are not as extensive, although small apical vesicles are abundant. The basement membrane is very thin. Magnification 311,000. Reproduced with permission from Tischer et al. (81). AV, apical vacuole; BM, basement membrane; Cs, autophagic vacuole (cytosergresome); TL, tubular lumen. diabetes.diabetesjournals.org Gilbert 793 milieu. In addition, however, recent studies suggest that the proximal tubule may also contribute to glomerulop- athy. In their seminal 2013 study, Hasegawa et al. (8) provide evidence of retrograde trafficking between the proximal tubule and the glomerulus, showing that nico- tinamide mononucleotide (NMN) released by proximal tubular epithelial cells diffuses back to the glomerulus to induce podocyte foot process effacement and albumin- uria (9) (Fig. 4). Given the importance of podocyte injury not only in the development of proteinuria but also in the progression of glomerulosclerosis and tubuloglomerular junction pathology (10), the triggering of glomerular pa- thology by the proximal tubule reinforces the primary importance of this region in disease development. We are, however, reminded of the importance of using mul- Figure 3—A photomicrograph of an atubular glomerulus showing tiple studies, preferably performed in different laborato- that while the glomerular tuft is indistinguishable from other glomer- ries using different animal models, to provide confidence uli, Bowman’s capsule is markedly thickened and wrinkled at a site for a new, potentially paradigm-shifting understanding in opposite to the vascular pole, where a tubular connection is expected how diabetic podocytopathy develops. but absent. PAS-stained; magnification 3630. Reproduced with per- fi mission from Najafian et al. (6). ↔,reduplicatedBowman’scapsule; Cognizant of the absence of signi cant albuminuria in arrowhead, a spindle-shape cell within the reduplicated Bowman’s many patients with declining GFR in diabetic kidney dis- capsule; arrows, atrophic tubules adjacent to the atubular glomerulus; ease, other studies show that proximal tubular injury leads *periglomerular fibrosis. not only to podocytopathy but also to more extensive glomerular injury. Using a mouse model of kidney disease